CRTH2 receptor ligands for medicinal uses

ABSTRACT

Compounds of formula (I) are useful for the treatment of disease responsive to modulation of CRTH2 receptor activity, such as asthma, rhinitis, allergic airway syndrome, and allergic rhinobronchitis: 
     
       
         
         
             
             
         
       
     
     wherein A represents a carboxyl group —COOH, or a carboxyl bioisostere; A 1  is hydrogen or methyl; ring Ar 1  is an optionally substituted phenyl ring or 5- or 6-membered monocyclic heteroaryl ring, in which AA 1 CHO— and L2 are linked to adjacent ring atoms; rings Ar 2 , Ar 3  each independently represent a phenyl or 5- or 6-membered monocyclic heteroaryl ring, or a bicyclic ring system consisting of a 5- or 6-membered carbocyclic or heterocyclic ring which is benz-fused or fused to a 5- or 6-membered monocyclic heteroaryl ring, said ring or ring system being optionally substituted; t is 0 or 1; L2 and L3 are linker radicals as defined in the description.

This application is a divisional of U.S. Ser. No. 11/597,873 filed Nov.29, 2006, now allowed, entitled CRTH2 Receptor Ligands For MedicinalUses, whereby U.S. Ser. No. 11/597,873 is a U.S. National Stageapplication of co-pending PCT application PCT/EP2005/005884, filed May30, 2005, which claims the priority of Great Britain Patent ApplicationNo. 0412198.4, filed May 29, 2004, Great Britain Patent Application No.0414196.6, filed Jun. 24, 2004 and Great Britain Patent Application No.0424018.0, filed Oct. 29, 2004. These applications are incorporatedherein by reference in their entireties.

This invention relates to the use of a class of compounds which areligands of the CRTH2 receptor (Chemoattractant Receptor-homologousmolecule expressed on T Helper cells type 2), in the treatment ofdiseases responsive to modulation of CRTH2 receptor activity,principally diseases having a significant inflammatory component. Theinvention also relates to novel members of that class of ligands andpharmaceutical compositions containing them.

Many classes of antiinflammatory agents are known, including thenon-steroidal antiinflammatory compounds known as NSAIDs and theinhibitors of cyclooxygenase (COX-1 and COX-2). Benzoylphenylacetic acidand some benzophenone derivatives with carboxymethoxy substituents inone of the rings have been identified as antiinflammatory agents (see,for example, Khanum et. al. Bioorganic Chemistry Vol 32, No. 4, 2004,pages 211-222 and the references cited therein). Some o-phenylcarbamoyl-phenoxyacetic acids and o-benzamido-phenoxymethyl tetrazoleshave been reported as potential antiinflammatory agent, see for exampleDrain et. al. J. Pharm. Pharmac., 1971, 23, 857-864, and ibid 1970, 22,684-693. WO 99/15520 discloses a few benzophenone derivatives withcarboxymethoxy or tetrazolylmethoxy substituents in one of the rings,synthesised as members of a group of compounds said to have activity asinhibitors of peroxisome proliferator-activated receptor (PPAR), andutility in a variety of disease states including diabetes, cardiacdisease, and circulatory disease.

The natural ligand of the G-protein coupled receptor CRTH2 isprostaglandin D2. As its name implies, CRTH2 is expressed on T helpercells type 2 (Th2 cells) but it is also known to be expressed oneosinophils and basophil cells. Cell activation as a result of bindingof PGD2 to the CRTH2 receptor results in a complex biological response,including release of inflammatory mediators. Elevated levels of PGD2 aretherefore associated with many diseases which have a strong inflammatorycomponent, such as asthma, rhinitis and allergies. Blocking binding ofPGD2 to the CRTH2 receptor is therefore a useful therapeutic strategyfor treatment of such diseases.

Some small molecule ligands of CRTH2, apparently acting as antagonistsof PGD2, are known, for example as proposed in the following patentpublications: WO 03/097042, WO 03/097598, WO 03/066046, WO 03/066047, WO03/101961, WO 03/101981, GB 2388540, WO 04/089885 and WO 05/018529.

The structures of PGD2 antagonist compounds referred to in some of theforegoing publications have a bicyclic or tricyclic core ring systemrelated to the indole core of indomethacin, a known anti-inflammatoryagent, now known to bind to CRTH2. The present invention arises from theidentification of a class of compounds having a monocyclic core whosesubstituent moieties are selected and orientated by the monocyclic coreto interact with and bind to CRTH2. The class of compounds with whichthis invention is concerned are thus capable of modulating CRTH2activity, and are useful in the treatment of diseases which benefit fromsuch modulation, for example asthma, allergy and rhinitis.

According to the present invention, there is provided the use of acompound of formula (I) or a salt, hydrate or solvate thereof in themanufacture of a composition for the treatment of disease responsive tomodulation of CRTH2 receptor activity:

wherein

A represents a carboxyl group —COOH, or a carboxyl bioisostere;

A₁ is hydrogen or methyl;

ring Ar¹ is an optionally substituted phenyl ring or 5- or 6-memberedmonocyclic heteroaryl ring, in which AA₁CHO— and L2 are linked toadjacent ring atoms;

rings Ar², Ar³ each independently represent a phenyl or 5- or 6-memberedmonocyclic heteroaryl ring, or a bicyclic ring system consisting of a 5-or 6-membered carbocyclic or heterocyclic ring which is benz-fused orfused to a 5- or 6-membered monocyclic heteroaryl ring, said ring orring system being optionally substituted;

t is 0 or 1;

L2 and L3 each independently represents a divalent radical of formula-(Alk¹)_(m)-(Z)_(n)-(Alk²)_(p) wherein

-   -   m, n and p are independently 0 or 1,    -   Alk¹ and Alk² are independently optionally substituted straight        or branched chain C₁-C₃ alkylene or C₂-C₃ alkenylene radicals        which may contain a compatible —O—, —S— or —NR— link wherein R        is hydrogen or C₁-C₃ alkyl, and    -   Z is —O—; —S—; —C(═O)—; —SO₂—; —SO—; —NR—, —NRSO₂—, —SO₂NR—,        —C(═O)NR—, —NRC(═O)—, —NRCONH—, —NHCONR—, —NRC(═NR)NH—,        —NHC(═NR)NR—, —C(R)═N—NR—, or —NR—N═C(R)— wherein R is hydrogen        or C₁-C₃ alkyl; or a divalent 5- or 6-membered monocyclic        carbocyclic or heterocyclic radical,

PROVIDED THAT

-   (A) the total length of L2 and L3 does not exceed that of an    unbranched saturated chain of 10 carbon atoms; and-   (B) L2 is not —C(═O)—, —C(═O)NR—, or —NRC(═O)— when Ar² is    optionally substituted phenyl; and-   (C) (a) L2 is not a bond and (b) p in L2 is not 0 when n is 1 and Z    is aryl or heteroaryl, and-   (D) (a) L2 is not —O—, —SO₂—, —NR—, —CHR^(X)R^(Y)— or    —CH(R^(X))(OR^(Y))—, wherein R^(X) and R^(Y) are independently    hydrogen, halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or    C₃-C₇ cycloalkyl, or join to form a ring, and (b) when p is 1 and n    is 1 and Z is aryl or heteroaryl then Alk² is not —CHR^(X)R^(Y)— or    —CH(R^(X))(OR^(Y))—, wherein R^(X) and R^(Y) are independently    hydrogen, halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or    C₃-C₇ cycloalkyl, or join to form a ring.

In one aspect of the invention, in compounds (I), the length of each ofL2 and L3 does not exceed that of an unbranched saturated chain of 5carbon atoms and (ii) the total length of L2 and L3 does not exceed thatof an unbranched saturated chain of 7 carbon atoms, and (iii) neither ofL2 and L3 includes more than two R substituents different from hydrogen.In a narrower aspect of the invention, compounds (I) as defined abovewherein A₁ is hydrogen and Z is —O—; —S—; —C(═O)—; —SO₂—; —SO—; —NR—,—NRSO₂—, —C(═O)NR—, —NRCONH—, —NRC(═NR)NH—, or —C(R)═N—NR—, wherein R ishydrogen or C₁-C₃ alkyl; or a divalent 5- or 6-membered monocycliccarbocyclic or heterocyclic radical, may be used

In another narrower aspect of the invention, compounds (I) as definedabove wherein L2 is —N═CR—, —OCR₂C(═O)NR—N═CR—, —C(═O)NR—, —N═CR—,—C(═O)—, —CH═CHC(═O)—(CH₂)₀₋₃NRC(═O)—, —NRC(═O)(CH₂)₀₋₃—, —O—N═CH—,—CH₂NRCH₂—, —NR(CH₂)₁₋₃—, —(CH₂)₁₋₃NR—, —S—, —CH₂OCH₂—, —O(CH₂)₁₋₃—,—(CH₂)₁₋₃O—, —CH₂SCH₂—, —S(CH₂)₀₋₃—, —(CH₂)₀₋₃S—, a divalent(C₂-C₆)alkylene radical, a divalent (C₂-C₆)alkenylene radical, or adivalent (C₂-C₆)alkynylene radical, wherein R is hydrogen or C₁-C₃alkyl, may be used

In further narrower aspects of the invention, compounds (I) as definedabove wherein L2 is —NRN═CH—, —ON═CH—, or —N═CH—; or L2 is —C(═O)—; orL2 is —NHC(═O)— or —C(═O)NH—, may be used.

An independent aspect of the invention is the use of a compound offormula (I) set out above or a salt, hydrate or solvate thereof in themanufacture of a composition for the treatment of disease responsive tomodulation of CRTH2 receptor activity, in which compound (I):

A represents a carboxyl group —COOH, or a carboxyl bioisostere;

A₁ is hydrogen or methyl;

ring Ar¹ is an optionally substituted phenyl ring or 5- or 6-memberedmonocyclic heteroaryl ring, in which AA₁CHO— and L2 are linked toadjacent ring atoms;

rings Ar², Ar³ each independently represent a phenyl or 5- or 6-memberedmonocyclic heteroaryl ring, or a bicyclic ring system consisting of a 5-or 6-membered carbocyclic or heterocyclic ring which is benz-fused orfused to a 5- or 6-membered monocyclic heteroaryl ring, said ring orring system being optionally substituted;

t is 0 or 1;

L3 represents a divalent radical of formula-(Alk¹)_(m)-(Z)_(n)-(Alk²)_(p) wherein

-   -   m, n and p are independently 0 or 1,    -   Alk¹ and Alk² are independently optionally substituted straight        or branched chain C₁-C₃ alkylene or C₂-C₃ alkenylene radicals        which may contain a compatible —O—, —S— or —NR— link wherein R        is hydrogen or C₁-C₃ alkyl, and    -   Z is —O—; —S—; —C(═O)—; —SO₂—; —SO—; —NR—, —NRSO₂—, —SO₂NR—,        —C(═O)NR—, —NRC(═O)—, —NRCONH—, —NHCONR—, —NRC(═NR)NH—,        —NHC(═NR)NR—, —C(R)═N—NR—, or —NR—N═C(R)— wherein R is hydrogen        or C₁-C₃ alkyl; or a divalent 5- or 6-membered monocyclic        carbocyclic or heterocyclic radical,

L2 represents a divalent radical selected from one of the followingformulae (sometimes called “L2 set A” herein), wherein either (i) thebond marked * is attached to Ar² while the bond marked ** is attached toAr¹, or (ii) the bond marked * is attached to Ar¹ while the bond marked** is attached to Ar²:

wherein R is hydrogen or C₁-C₃ alkyl; and

the total length of L2 and L3 does not exceed that of an unbranchedsaturated chain of 10 carbon atoms.

In a narrower definition of this aspect of the invention, in thecompounds (I), (i) the length of L3 does not exceed that of anunbranched saturated chain of 5 carbon atoms and (ii) the total lengthof L2 and L3 does not exceed that of an unbranched saturated chain of 7carbon atoms, and (iii) L3 does not include more than two R substituentsdifferent from hydrogen.

In the two immediately foregoing aspects of the invention, in thecompounds (I), A1 may be hydrogen and L2 may be one of the followingformulae (sometimes called “L2 set B” herein) wherein the bond marked *is attached to Ar² while the bond marked ** is attached to Ar¹:

wherein R is hydrogen or C₁-C₃ alkyl.

The compounds with which the invention is concerned are defined byreference to formula (I) as a result of studies towards elucidation ofthe ligand binding site of CRTH2. Such studies led to the overallconclusion that a general pharmacophore comprising one negativelycharged moiety, represented by AA₁CHO—, and two aromatic and/orhydrophobic moieties, represented by Ar²L2 and either H(Ar³)_(t)L3-Ar¹or only Ar¹, oriented in an approximate triangle, would form anarrangement for interaction with the receptor binding site. It wasconcluded that the substituent groupings AA₁CHO— and Ar²L2- should be onadjacent ring atoms of Ar¹. The linkers L2 and L3 provide someflexibility to the molecule to facilitate optimum binding. Therestrictions on the lengths of, and substitutions in, the linkers L2 andL3 are in order to restrict the total molecular size and complexity ofstructures for use in accordance with the invention. For the avoidanceof doubt, the total length of L2 and L3 is, for the purposes of thisdescription and claims, the sum n2+n3, where n2 is the number ofconnected atoms in the shortest chain of atoms from terminal atom toterminal atom of linker L2, and n3 is the number of connected atoms inthe shortest chain of atoms from terminal atom to terminal atom oflinker L2. Preferably the compounds with which the invention isconcerned should have a molecular weight of no more than 600. Optionalsubstituents in any element of the compounds (I) are permitted as in thedefinition of compounds (I). Such substituents can modulatepharmacokinetic and solubility properties, as well as picking upadditional binding interactions with the receptor.

In another aspect, the invention provides a method of treatment of asubject suffering from a disease responsive to modulation of CRTH2receptor activity, which comprised administering to the subject anamount of a compound (I) as defined and described above effective toameliorate the disease.

In particular, compounds with which the invention is concerned areuseful in the treatment of disease associated with elevated levels ofprostaglandin D2 (PGD2) or one or more active metabolites thereof.

Examples of such diseases include asthma, rhinitis, allergic airwaysyndrome, allergic rhinobronchitis, bronchitis, chronic obstructivepulmonary disease (COPD), nasal polyposis, sarcoidosis, farmer's lung,fibroid lung, cystic fibrosis, chronic cough, conjunctivitis, atopicdermatitis, Alzheimer's disease, amyotrophic lateral sclerosis, AIDSdementia complex, Huntington's disease, frontotemporal dementia, Lewybody dementia, vascular dementia, Guillain-Barre syndrome, chronicdemyelinating polyradiculoneurophathy, multifocal motor neuropathy,plexopathy, multiple sclerosis, encephalomyelitis, panencephalitis,cerebellar degeneration and encephalomyelitis, CNS trauma, migraine,stroke, rheumatoid arthritis, ankylosing spondylitis, Behçet's Disease,bursitis, carpal tunnel syndrome, inflammatory bowel disease, Crohn'sdisease, ulcerative colitis, dermatomyositis, Ehlers-Danlos Syndrome(EDS), fibromyalgia, myofascial pain, osteoarthritis (OA),osteonecrosis, psoriatic arthritis, Reiter's syndrome (reactivearthritis), sarcoidosis, scleroderma, Sjogren's Syndrome, soft tissuedisease, Still's Disease, tendinitis, polyarteritis Nodossa, Wegener'sGranulomatosis, myositis (polymyositis dermatomyositis), gout,atherosclerosis, lupus erythematosus, systemic lupus erythematosus(SLE), type I diabetes, nephritic syndrome, glomerulonephritis, acuteand chronic renal failure, eosinophilia fascitis, hyper IgE syndrome,sepsis, septic shock, ischemic reperfusion injury in the heart,allograft rejection after transplantations, and graft versus hostdisease.

However, the compounds with which the invention is concerned areprimarily of value for the treatment asthma, rhinitis, allergic airwaysyndrome, and allergic rhinobronchitis.

Many compounds of formula (I) above are novel in their own right, andthe invention includes such novel compounds per se.

As used herein, the term “(C₂-C_(b))alkyl” wherein a and b are integersrefers to a straight or branched chain alkyl radical having from a to bcarbon atoms. Thus when a is 1 and b is 6, for example, the termincludes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, n-pentyl and n-hexyl.

As used herein the term “divalent (C_(a)-C_(b))alkylene radical” whereina and b are integers refers to a saturated hydrocarbon chain having froma to b carbon atoms and two unsatisfied valences.

As used herein the term “(C₂-C_(b))alkenyl” wherein a and b are integersrefers to a straight or branched chain alkenyl moiety having from a to bcarbon atoms having at least one double bond of either E or Zstereochemistry where applicable. The term includes, for example, vinyl,allyl, 1- and 2-butenyl and 2-methyl-2-propenyl.

As used herein the term “divalent (C_(a)-C_(b))alkenylene radical” meansa hydrocarbon chain having from a to a carbon atoms, at least one doublebond, and two unsatisfied valences.

As used herein the term “C_(a)-C_(b) alkynyl” wherein a and b areintegers refers to straight chain or branched chain hydrocarbon groupshaving from two to six carbon atoms and having in addition one triplebond. This term would include for example, ethynyl, 1- and 2-propynyl,1-, 2- and 3-butynyl, 1, 2-, 3- and 4-pentynyl, 1-, 2-, 3-, 4- and5-hexynyl, 3-methyl-1-butynyl, 1-methyl-2-pentynyl.

As used herein the term “divalent (C_(a)-C_(b))alkynylene radical”wherein a and b are integers refers to a divalent hydrocarbon chainhaving from 2 to 6 carbon atoms, at least one triple bond, and twounsatisfied valences.

As used herein the term “carbocyclic” refers to a mono-, bi- ortricyclic radical having up to 16 ring atoms, all of which are carbon,and includes aryl and cycloalkyl.

As used herein the term “cycloalkyl” refers to a monocyclic saturatedcarbocyclic radical having from 3-8 carbon atoms and includes, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyland cyclooctyl.

As used herein the unqualified term “aryl” refers to a mono-, bi- ortri-cyclic carbocyclic aromatic radical, and includes radicals havingtwo monocyclic carbocyclic aromatic rings which are directly linked by acovalent bond. Illustrative of such radicals are phenyl, biphenyl andnapthyl.

As used herein the unqualified term “heteroaryl” refers to a mono-, bi-or tri-cyclic aromatic radical containing one or more heteroatomsselected from S, N and O, and includes radicals having two suchmonocyclic rings, or one such monocyclic ring and one monocyclic arylring, which are directly linked by a covalent bond. Illustrative of suchradicals are thienyl, benzthienyl, furyl, benzfuryl, pyrrolyl,imidazolyl, benzimidazolyl, thiazolyl, benzthiazolyl, isothiazolyl,benzisothiazolyl, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl,benzisoxazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl,oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyridazinyl,triazinyl, indolyl and indazolyl.

As used herein the unqualified term “heterocyclyl” or “heterocyclic”includes “heteroaryl” as defined above, and in addition means a mono-,bi- or tri-cyclic non-aromatic radical containing one or moreheteroatoms selected from S, N and O, and to groups consisting of amonocyclic non-aromatic radical containing one or more such heteroatomswhich is covalently linked to another such radical or to a monocycliccarbocyclic radical. Illustrative of such radicals are pyrrolyl,furanyl, thienyl, piperidinyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl,pyrimidinyl, morpholinyl, piperazinyl, indolyl, morpholinyl,benzfuranyl, pyranyl, isoxazolyl, benzimidazolyl, methylenedioxyphenyl,ethylenedioxyphenyl, maleimido and succinimido groups.

The term “carboxyl bioisostere” is a term familiar to medicinal chemists(see for example “The Organic Chemistry of Drug Design and Drug Action”,by Richard B. Silverman, pub. Academic Press, 1992), and refers to agroup which has similar acid-base characteristics to those of a carboxylgroup. Well known carboxyl bioisosteres include —SO₂NHR or—P(═O)(OH)(OR) wherein R is, for example, hydrogen methyl or ethyl,—SO₂OH, —P(═O)(OH)(NH₂), —C(═O)NHCN and groups of formulae:

Unless otherwise specified in the context in which it occurs, the term“substituted” as applied to any moiety herein means substituted with upto four compatible substituents, each of which independently may be, forexample, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy, hydroxy(C₁-C₆)alkyl,mercapto, mercapto(C₁-C₆)alkyl, (C₁-C₆)alkylthio, halo (includingfluoro, bromo and chloro), fully or partially fluorinated (C₁-C₃)alkyl,(C₁-C₃)alkoxy or (C₁-C₃)alkylthio such as trifluoromethyl,trifluoromethoxy, and trifluoromethylthio, nitro, nitrile (—CN), oxo,phenyl, phenoxy, —COOR^(A), —COR^(A), —OCOR^(A), —SO₂R^(A),—CONR^(A)R^(B), —SO₂NR^(A)R^(B), —NR^(A)R^(B), —OCONR^(A)R^(B),—NR^(B)COR^(A), —NR^(B)COOR^(A), —NR^(B)SO₂OR^(A) or—NR^(A)CONR^(A)R^(B) wherein R^(A) and R^(B) are independently hydrogenor a (C₁-C₆)alkyl group or, in the case where R^(A) and R^(B) are linkedto the same N atom, R^(A) and R^(B) taken together with that nitrogenmay form a cyclic amino ring. Where the substituent is phenyl orphenoxy, the phenyl ring thereof may itself be substituted by any of theabove substituents except phenyl or phenoxy. An “optional substituent”may be one of the foregoing substituent groups.

As used herein the term “salt” includes base addition, acid addition andquaternary salts. Compounds of the invention which are acidic can formsalts, including pharmaceutically acceptable salts, with bases such asalkali metal hydroxides, e.g. sodium and potassium hydroxides; alkalineearth metal hydroxides e.g. calcium, barium and magnesium hydroxides;with organic bases e.g. N-methyl-D-glucamine, cholinetris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethylpiperidine, dibenzylamine and the like. Those compounds (I) which arebasic can form salts, including pharmaceutically acceptable salts withinorganic acids, e.g. with hydrohalic acids such as hydrochloric orhydrobromic acids, sulphuric acid, nitric acid or phosphoric acid andthe like, and with organic acids e.g. with acetic, tartaric, succinic,fumaric, maleic, malic, salicylic, citric, methanesulphonic,p-toluenesulphonic, benzoic, benzenesunfonic, glutamic, lactic, andmandelic acids and the like.

Compounds with which the invention is concerned which may exist in oneor more stereoisomeric form, because of the presence of asymmetric atomsor rotational restrictions, can exist as a number of stereoisomers withR or S stereochemistry at each chiral centre or as atropisomeres with Ror S stereochemistry at each chiral axis. The invention includes allsuch enantiomers and diastereoisomers and mixtures thereof.

Use of prodrugs, such as esters, of compounds (I) with which theinvention is concerned is also part of the invention.

For use in accordance with the above aspects of the invention thefollowing structural characteristics may be present, in any compatiblecombination, in the compounds (I):

-   -   L2 may be a member of L2 set A above (and of course L2 set A        includes L2 set B);    -   L2 may be —N═CR—, —OCR₂C(═O)NR—N═CR—, —C(═O)NR—, —N═CR—,        —C(═O)—, —CH═CHC(═O)—(CH₂)₀₋₃NRC(═O)—, —NRC(═O)(CH₂)₀₋₃—,        —O—N═CH—, —CH₂NRCH₂—, —NR(CH₂)₁₋₃—, —(CH₂)₁₋₃NR—, —S—,        —CH₂OCH₂—, —O(CH₂)₁₋₃—, —(CH₂)₁₋₃O—, —CH₂SCH₂—, —S(CH₂)₀₋₃—,        —(CH₂)₀₋₃S—, a divalent (C₂-C₆)alkylene radical, a divalent        (C₂-C₆)alkenylene radical, or a divalent (C₂-C₆)alkynylene        radical, wherein R is hydrogen or C₁-C₃ alkyl;    -   L2 may be —NRN═CH—, —ON═CH—, —N═CH—, —C(═O)—, —NHC(═O)— or        —C(═O)NH—;    -   Ar² may be an optionally substituted phenyl or 5- or 6-membered        nitrogen-containing heteroaryl ring, for example pyridyl,        pyrimidyl, diazolyl, thiazolyl, oxazolyl, triazinyl, quinolinyl,        pyrrollyl, furanyl, thiazolyl;    -   Optional substituents in Ar² may be selected from fluoro,        chloro, bromo, (C₁-C₃)alkyl, trifluoromethyl, (C₁-C₃)alkoxy,        trifluoromethoxy, trifluoromethylthio, dimethylamino, cyano,        (C₁-C₃alkyl)SO₂—, NH₂SO₂—, (C₁-C₃alkyl)NHSO₂—,        (C₁-C₃alkyl)₂NSO₂—, and nitro;    -   Ar¹ may be an optionally substituted 5- or 6-membered        nitrogen-containing heteroaryl ring, for example pyridyl,        pyrimidyl, diazolyl, thiazolyl, oxazolyl, triazinyl, quinolinyl,        pyrrollyl, furanyl, thiazolyl, and wherein L3 may be linked to a        ring carbon in (for a 6-membered ring) the 4 position thereof        relative to the ACHA₁O— radical or (for a 5-membered ring) the 4        position thereof counting the ACHA₁O— radical as in position 1        and the Ar²L2-radical as in position 2 thereof;    -   Ar¹ may be an optionally substituted phenyl ring wherein L3 is        linked to the 4 position thereof relative to the ACHA₁O-radical;    -   when t is 1, Ar³ may be an optionally substituted phenyl ring,        or an optionally substituted 5- or 6-membered heteroaryl ring,        for example pyridyl, pyrimidyl, diazolyl, thiazolyl, oxazolyl,        triazinyl, quinolinyl, pyrrollyl, furanyl, or thiazolyl;    -   optional substituents in ring Ar¹ or Ar³ may be selected from        fluoro, chloro, bromo, iodo, cyano, nitro, trifluoromethyl,        trifluoromethoxy, trifluoromethylthio, (C₁-C₃alkyl)SO₂—,        NH₂SO₂—, (C₁-C₃alkyl)NHSO₂—, (C₁-C₃alkyl)₂NSO₂—, C₁-C₆ alkyl,        C₁-C₆ alkoxy, cycloalkyl, aryl, aryloxy, aryl(C₁-C₆₎₋ or        aryl(C₁-C₆ alkoxy)-;    -   when t is 0, L3 may be a bond;    -   A may be —COOH or a carboxyl bioisostere selected from —SO₂NHR        and —P(═O)(OH)(OR) wherein R is hydrogen methyl or ethyl,        —SO₂OH, —P(═O)(OH)(NH₂), —C(═O)NHCN and groups of formulae:

-   -   It is currently preferred that A be carboxyl;    -   A₁ may be hydrogen or methyl.

Compounds (I) for use in accordance with the invention include those offormula (IV) and salts, hydrates or solvates thereof, which are believednovel per se, and which form another aspect of the invention:

wherein A, A1, L3, Ar³, Ar², and t are as defined and discussed above inrelation to formula (I), R13 represents hydrogen or one or more optionalsubstituents, and L2 is a member of the L2 set A, as defined above. Thisincludes the case where A_(l) is hydrogen and L2 is a member of the L2set B as defined above.

The following structural characteristics may be present in compounds(IV), in any compatible combination:

A may be —COOH, or a carboxyl bioisostere selected from —SO₂NHR and—P(═O)(OH)(OR) wherein R is hydrogen methyl or ethyl, —SO₂OH,—P(═O)(OH)(NH₂), —C(═O)NHCN and groups of formulae:

Currently it is preferred that A be carboxyl.

R₁₃ may represent one or more substituents selected from fluoro, chloro,bromo, iodo, cyano, nitro, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, (C₁-C₃alkyl)SO₂—, NH₂SO₂—, (C₁-C₃alkyl)NHSO₂—,(C₁-C₃alkyl)₂NSO₂—, C₁-C₆ alkyl, C₁-C₆ alkoxy, cycloalkyl, aryl,aryloxy, aryl(C₁-C₆₎₋ or aryl(C₁-C₆ alkoxy)-.

A₁ may be methyl or A₁ may be hydrogen.

One preferred subset of the compounds (IV) has formula (IVA)

wherein A, A₁ L3, t, Ar³, R₁₃ are as defined and discussed above inrelation to compounds of formula (I) and (IV) and R₁₄ is optionallysubstituted phenyl or 5- or 6-membered heteroaryl.

Another preferred subset of the compounds (IV) has formula (IVB):

wherein A₁, L3, t, and Ar³ are as defined and discussed above inrelation to formulae (I), (IV) and (IVA), and R₁₄ is optionallysubstituted phenyl or 5- or 6-membered heteroaryl

Another preferred subset of the compounds (IV) has formula (IVC):

wherein R₁₃ represents a substituent selected from fluoro, chloro,bromo, iodo, (C₁-C₆)alkyl, trifluoromethyl, (C₁-C₆)alkoxy,(C₁-C₆)alkylmercapto, trifluoromethoxy, trifluoromethylthio,dimethylamino, cyano, (C₁-C₃alkyl)SO₂—, NH₂SO₂—, (C₁-C₃alkyl)NHSO₂—,(C₁-C₃alkyl)₂NSO₂—, and nitro, and R₁₄ is optionally substituted phenylor 5- or 6-membered heteroaryl. In this subset, R₁₄ may be a2-substituted, 2,4-disubstituted, 2,6-disubstituted or2,4,6-trisubstituted phenyl ring where the substituents are selectedfrom fluoro, chloro, bromo, iodo, (C₁-C₆)alkyl, trifluoromethyl,(C₁-C₆)alkoxy, (C₁-C₆)alkylmercapto, trifluoromethoxy,trifluoromethylthio, dimethylamino, (C₁-C₃alkyl)SO₂—, NH₂SO₂—,(C₁-C₃alkyl)NHSO₂—, (C₁-C₃alkyl)₂NSO₂—, and cyano. This subsetspecifically includes compounds wherein A₁ is hydrogen.

In any compound (I), (IV) (IVA), (IVB) or IVC) defined and discussedabove, wherein A1 is methyl, the carbon atom to which it is attachedpreferably has the S stereochemical configuration.

Specific novel compounds of the invention are the following:

4-chloro-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetic acid,

4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetic acid,

[4-bromo-2-(1-pyridin-2-yl-1H-pyrazole-4-carbonyl)phenoxy]acetic acid,

{4-bromo-2-[1-(2-chlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

{4-bromo-2-[1-(3-chlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

{4-bromo-2-[1-(4-bromophenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

{4-bromo-2-[1-(4-chlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

{4-bromo-2-[1-(2-ethylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

{4-bromo-2-[1-(2-bromophenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

{4-bromo-2-[1-(2-fluorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

{4-bromo-2-[1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

{4-bromo-2-[1-(3-bromophenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

{4-bromo-2-[1-(2,4-dichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

{2-[1-(2-chlorophenyl)-1H-pyrazole-4-carbonyl]-4-nitrophenoxy}aceticacid,

{4-bromo-2-[1-(2,6-dichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

{2-[1-(2-bromophenyl)-1H-pyrazole-4-carbonyl]-4-ethylphenoxy}aceticacid,

{4-bromo-2-[1-(2,4-dibromophenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

{4-bromo-2-[1-(4-bromo-2-chlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

{4-bromo-2-[1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

2-[4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]propionic acid,

(S)-2-[4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]propionicacid,

2-{4-Bromo-2-[1-(2-chlorophenyl)-1-H-pyrazole-4-carbonyl]phenoxy}propionicacid,

(S)-2-{4-Bromo-2-[1-(2-chlorophenyl)-1-H-pyrazole-4-carbonyl]phenoxy}

propionic acid,

2-{4-Bromo-2-[1-(2,6-dichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid,

(S)-2-{4-Bromo-2-[1-(2,6-dichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid,

{4-Bromo-2-[1-(2-ethoxyphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

{4-Bromo-2-[1-(4-bromo-2-ethylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

{4-Bromo-2-[1-(2-phenoxyphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

{4-Bromo-2-[1-(2-methylthiophenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

{4-Bromo-2-[1-(2-bromo-4-methylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

2-{4-Bromo-2-[1-(4-bromo-2-ethylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid,

2-{4-Bromo-2-[1-(2-phenoxyphenyl)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid,

(S)-2-{4-Bromo-2-[1-(2-phenoxyphenyl)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid,

2-{4-Bromo-2-[1-(2-methylthio)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid,

(S)-2-{4-Bromo-2-[1-(2-methylthio)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid,

{4-Bromo-2-[1-(2,4-dimethylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

{4-Bromo-2-[1-(4-chloro-2-methylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

{4-Bromo-2-[1-(2,5-dichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

2-{4-Bromo-2-[1-(4-chloro-2-methylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid,

2-{4-Bromo-2-[1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid,

{4-Bromo-2-[1-(2,6-diethyl-phenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

{4-Bromo-2-[1-(2,6-dimethylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid

{4-Bromo-2-[1-(2-ethyl-6-methylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

{4-Bromo-2-[1-(2-chloro-6-methylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

{4-Bromo-2-[1-(3,5-dichloropyridin-4-yl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid,

[4-Bromo-2-(1-naphthalen-1-yl-1H-pyrazole-4-carbonyl)phenoxy]aceticacid,

{4-Bromo-2-[2-(4-chlorobenzyl)thiazol-4-yl]phenoxy}acetic acid,

{4-Bromo-2-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}aceticacid,

{4-Bromo-2-[3-(4-methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}aceticacid,

{4-Bromo-2-[3-(4-chlorophenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}aceticacid,

{4-Bromo-2-[3-(4-fluoro-benzyl)-[1,2,4]oxadiazol-5-yl]-phenoxy}-aceticacid,

{4-Bromo-2-[3-(2,6-dichloro-benzyl)-[1,2,4]oxadiazol-5-yl]-phenoxy}-aceticacid,

{4-Bromo-2-[3-(2-trifluoromethylbenzyl)-[1,2,4]oxadiazol-5-yl]phenoxy}-aceticacid,

4-Bromo-2-[3-(2,6-dichloro-phenyl)isoxazole-5-carbonyl]phenoxy}aceticacid,

{4-Bromo-2-[3-(1-phenylcyclopropyl)-[1,2,4]oxadiazol-5-yl]phenoxy}aceticacid,

{4-Bromo-2-[3-(2,4-dichlorophenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}aceticacid,

-   -   and salts, hydrates and solvates thereof.

The invention also includes pharmaceutical compositions comprising acompound belonging to the above described compounds of formula (IV),(IVA), (IVB) or (IVC), together with a pharmaceutically acceptablecarrier.

Compositions

As mentioned above, the compounds with which the invention is concernedare capable of modulating CRTH2 activity, and are useful in thetreatment of diseases which benefit from such modulation. Examples ofsuch diseases are referred to above, and include asthma, allergy andrhinitis.

It will be understood that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, rate ofexcretion, drug combination and the severity of the particular diseaseundergoing treatment. Optimum dose levels and frequency of dosing willbe determined by clinical trial, as is required in the pharmaceuticalart.

The compounds with which the invention is concerned may be prepared foradministration by any route consistent with their pharmacokineticproperties. The orally administrable compositions may be in the form oftablets, capsules, powders, granules, lozenges, liquid or gelpreparations, such as oral, topical, or sterile parenteral solutions orsuspensions. Tablets and capsules for oral administration may be in unitdose presentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricant, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants for example potato starch, or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, glucose syrup, gelatin hydrogenated ediblefats; emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, fractionated coconut oil, oily esters such asglycerine, propylene glycol, or ethyl alcohol; preservatives, forexample methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents.

For topical application to the skin, the drug may be made up into acream, lotion or ointment. Cream or ointment formulations which may beused for the drug are conventional formulations well known in the art,for example as described in standard textbooks of pharmaceutics such asthe British Pharmacopoeia.

For topical application to the eye, the drug may be made up into asolution or suspension in a suitable sterile aqueous or non aqueousvehicle. Additives, for instance buffers such as sodium metabisulphiteor disodium edeate; preservatives including bactericidal and fungicidalagents such as phenyl mercuric acetate or nitrate, benzalkonium chlorideor chlorhexidine, and thickening agents such as hypromellose may also beincluded.

The drug may also be formulated for inhalation, for example as a nasalspray, or dry powder or aerosol inhalers.

The active ingredient may also be administered parenterally in a sterilemedium. Depending on the vehicle and concentration used, the drug caneither be suspended or dissolved in the vehicle. Advantageously,adjuvants such as a local anaesthetic, preservative and buffering agentscan be dissolved in the vehicle.

The compounds with which the invention is concerned may be administeredalone, or as part of a combination therapy with other drugs used fortreatment of diseases with a major inflammatory component. In the caseof asthma, rhinitis, and allergic airway syndrome such drugs includecorticosteroids, long-acting inhaled beta agonists, cromolyn,nedocromil, theophylline, leukotriene receptor antagonists,antihistamines, and anticholinergics (e.g. ipratropium), and are oftenadministered as nasal sprays, dry powder or aerosol inhalers.

In the case of arthritis and related inflammatory diseases other knowndrugs include glucocorticoids, NSAIDs (Non Steroidal Anti-InflammatoryDrugs—conventional prostaglandin synthesis inhibitors, COX-2 inhibitors,salicylates), and DMARDs (disease-modifying anti-rheumatic drugs such asmethotrexate, sulfasalazine, gold, cyclosporine).

Synthetic Routes

There are multiple synthetic strategies for the synthesis of thecompounds (I) with which the present invention is concerned, but allrely on known chemistry, known to the synthetic organic chemist. Thus,compounds according to Formula I can be synthesised according toprocedures described in the standard literature and are well-known tothe one skilled in the art. Typical literature sources are “Advancedorganic chemistry”, 4^(th) Edition (Wiley), J March, “ComprehensiveOrganic Transformation”, 2^(nd) Edition (Wiley), R. C. Larock ,“Handbook of Heterocyclic Chemistry”, 2^(nd) Edition (Pergamon), A. R.Katritzky), review articles such as found in “Synthesis”, “Acc. Chem.Res.”, “Chem. Rev”, or primary literature sources identified by standardliterature searches online or from secondary sources such as “ChemicalAbstracts” or “Beilstein”.

In the discussion which follows, A represents a carboxylic acid, acarboxyl bioisostere, or a protected carboxylic acid or bioisostere, ora precursor of these. In the latter case, a deprotection step isimplied. A₁ represents hydrogen or methyl.

Many compounds claimed in this invention may be synthesized by reactinga phenol precursor with LG-CH(A₁)-A, where LG is a leaving group and Ais a carboxylic acid or a protected analog or precursor, or abioiosotere or a protected analog of this.

The linker L2 can be formed by joining two appropriately functionalisedand, if needed, suitably protected fragments containing La2 and Lb2 asreactive moieties as outlined below. La2 and Lb2 are defined as anymoieties that can react by e.g. a nucleophilic substitution, addition tomultiple bonds or cyclisation reaction to form a given L2 linker asexemplified below.

For example, the linker -L2- being -Alk¹-Z-(Alk²)_(p)- can be formed byreacting Ar²-Alk¹- “leaving group” with a nucleophilic derivativeH—Z-(Alk²)_(p)-Ar¹(L1A)L3Ar³H wherein Z could be O, S or NR and Alk¹could be an alkyl group. The reactions can also be made by reversing thefunctionalisation of La2 and Lb2 to make the connection between Z andAlk². The linkers wherein Z is SO or SO₂ can be obtained by oxidationsof the corresponding -(Alk¹)_(m)-S-(Alk²)_(p)- derivatives duringappropriate conditions.

Further representative examples, -L2- being -Alk¹-Z-(Alk²)_(p)- whereinZ is NH(CO) or NHSO₂ can be formed by reacting Ar²-(Alk¹)-NH₂ with anacylating derivative “leaving group”-CO-(Alk²)_(p)-Ar¹(L1A)L3Ar³H or“leaving group”-SO₂-(Alk²)_(p)-Ar¹(L1A)L3Ar³H, respectively.Alternatively, the conversion can be made directly with the acidsHO—CO-(Alk²)_(p)-Ar¹(L1A)L3Ar³H and HO—SO₂-(Alk²)_(p)-Ar¹(L1A)L3Ar³H,respectively, using suitable coupling reagents such asdicyclohexylcarbodiimide (DCC), and promoters such as1-hydroxybenzotriazole. Analogously, -L2- being -Alk¹-Z-(Alk²)_(p)-wherein Z being NH(CO)NH can be formed by reacting Ar²-(Alk¹)-NH₂ withan isocyanate derivative OCN-(Alk²)_(p)-Ar¹(L1A)L3Ar³H using suitableacid or base catalysis. The reactions can also be made by reversing thefunctionalisation of La2 and Lb2 to provide the “retro-bonds” in thecase of NH(CO) or NHSO₂. Analogously, the connections can be madebetween Z and Alk².

A metal catalyzed coupling reaction like the Stille coupling reaction,the Suzuki coupling reaction, the Heck reaction and the Sonogashirareaction are useful in the synthesis of examples with L2 being andivalent alkylene radical, a divalent alkenylene radical or a divalentalkynylene radical.

Compounds with L2 being a hydrazone are usually conveniently formed by acondensation reaction between the corresponding hydrazines and aldehydesin ethanol or without solvent.

Likewise, L2 being -(Alk¹)_(m)-Z-(Alk²)_(p)- wherein Z is a 5-memberedheterocyclic system exemplified by, for example,

can be made according to standard cyclisation procedures usingappropriate solvents, catalysts and temperatures. For example, formationof 1,2,4-triazole can be made with La2 being acylhydrazide and Lb2 beingamide or thioamide or the reverse orientation of La2 and Lb2.1,2,4-Oxadiazole can be formed from La2 being amidoxime and Lb2 beingcarboxylic ester or the reverse orientation of La2 and Lb2.1,3,4-Oxadiazole can be formed from La2 being acylhydrazide and Lb2being carboxylic ester or the reverse orientation of La2 and Lb2. Thethiazole can be made from La2 being thioamide and Lb2 being anα-haloketone or the reverse orientation of La2 and Lb2. The isoxazolecan be made from La2 being alkyne and Lb2 being nitriloxide or thereverse orientation in a cylcoaddition reaction.

In an analogous manner the compounds of formula I can be made by formingthe linker L3, according to procedures outlined for L2, as depictedbelow. Thus, La and Lb are defined as any moieties that can react bye.g. a nucleophilic substitution, addition to multiple bonds orcyclisation reaction to form a given linker as exemplified below.

The Ar¹ moiety can also be the central scaffold that is used inconnecting the L2 and L3 parts in a stepwise fashion. This can be donevia aromatic substitutions of the Ar¹ core to attach L2 and/or L3, whichthen can be further functionalised to give the final Formula Icompounds.

Furthermore, the Ar¹ moiety can also be assemblied via ring cyclisationreactions with reactants containing the L2 and L3 units eithercontaining the full appendices as outlined below:

or in forms that can be further functionalised into the final Formula Istructures as described previously. One such illustration is given below

For example, 1,2,4-triazoles can be made from acylhydrazides and amidesor thioamides; 1,2,4-Oxadiazoles from amidoximes and carboxylic esters;1,3,4-Oxadiazoles from acylhydrazides and carboxylic esters; Thiazolesfrom thioamides and α-haloketones; Pyridines via various cycloadditionreactions.

The building blocks used in the reactions are either commerciallyavailable or made according to standard procedures well-know to oneskilled in the art as described in “Advanced organic chemistry”, 4^(th)Edition (Wiley), J March, “Comprehensive Organic Transformation”, 2^(nd)Edition (Wiley), R. C. Larock, “Handbook of Heterocyclic Chemistry',2^(nd) Edition (Pergamon), A. R. Katritzky or other suitable literaturesources. The Examples herein describe specific strategies for thesynthesis of compounds wherein Ar¹ is phenyl. Analogous compounds areaccessible by variation of the intermediates used in the Examples.

The following Examples illustrate the preparation of compounds withwhich this invention is concerned. Some compounds were synthesised, andsome were acquired from commercial sources. In the Examples:

General Comments:

Microwave chemistry was performed in a Personal Chemistry EmrysOptimizer. NMR spectra were obtained on a Bruker Avance AMX 300 MHzinstrument. LC/MS was performed on an Agilent 1100-series instrument.LC/MS methods are as follows: An10p8: Column: XTerra MS C18; Flow: 1.0mL/min; Gradient: 0-5 min: 15-100% MeCN in water, 5-7½ min: 100% MeCN;Modifier: 5 mM ammonium formate; MS-ionisation mode: API-ES (pos.).An10n8: Column: XTerra MS C18; Flow: 1.0 mL/min; Gradient: 0-5 min:15-100% MeCN in water, 5-7½ min: 100% MeCN; Modifier: 5 mM ammoniumformate; MS-ionisation mode: API-ES (neg.).

General Synthetic Route I

General Synthetic Route II

General Procedure 1 (GP1):

Condensation of 3-formylchromone with arylhydrazine

The 3-formylchromone (1.0 mmol) and the arylhydrazine (1.0 mmol) inethanol (3.0 mL) in a reaction tube was added 4.0 M aq. KOH (1.0 mL, 4.0mmol). The tube was sealed and heated by microwaves to 120° C. for 7 min(420 s). The reaction mixture was added 3% HCl until pH<1 and left toprecipitated. The precipitate was filtered off and washed with a smallamount of ethanol. The product was used directly or purified byrecrystallisation from ethanol or by flash chromatography.

General Procedure 2 (GP2):

Alkylation of Phenol

The phenol (0.5 mmol) in acetone (1 mL) was added ethyl bromoacetate (85mg, 0.5 mmol) or ethyl 2-bromopropionate (91 mg, 0.5 mmol) and K₂CO₃ (75mg, 0.54 mmol), and the reaction mixture was stirred at room temperaturefor 12 h. The reaction mixture was then concentrated in vacuo and theresidue was partitioned between water and ethyl acetate. The organicphase was washed with brine, dried (MgSO₄) and concentrated. The productwas used directly or purified by recrystallization from MeOH or by flashchromatography.

General Procedure 3 (GP3):

Hydrolysis of Ester

The ester (0.10 mmol) in THF (0.5 mL) was added LiOH.H₂O (6.3 mg, 0.15mmol) in water (0.5 mL). The reaction was stirred at room temperaturefor >2 h, 3% HCl was added until pH<1, and the mixture was extractedwith CH₂Cl₂. The organic phase was dried (MgSO₄) and concentrated togive the product.

General Procedure 4 (GP4):

Suzuki Coupling/Ester Hydrolysis

Aryl bromide (0.20 mmol), aryl boronic acid (0.21 mmol) and Pd(PPh₃)₂Cl₂(9 mg, 0.01 mmol) was added MeCN (0.4 mL, degassed) and 1.0 M Na₂CO₃(0.4 mL, degassed). The reaction mixture was degassed by letting argonthrough for ½ min and heated by microwaves (150° C., 300 s), then added3% HCl until pH<1 and extracted with CH₂Cl₂. The extract was filteredthrough celite and concentrated, and the residue was purified bysolid-phase extraction (pre-packed 1 g SAX columns), or by flashchromatography.

INTERMEDIATE-1

Ethyl 4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetate.Prepared from(5-bromo-2-hydroxy-phenyl)-(1-phenyl-1H-pyrazol-4-yl)ketone and ethylbromoacetate according to GP2 to give 215 mg (100%) white crystals. Theproduct was used without further purification: LC/MS (an10p8): Rt 6.15min, m/z 429 [M+H]⁺; ¹H NMR (CDCl₃): δ 1.26 (t, J=7.1 Hz, 3H), 4.24 (q,J=7.1 Hz, 2H), 4.64 (s, 2H), 6.72 (d, J=8.9 Hz, 1H), 7.34 (m, 1H), 7.46(m, 2H), 7.53 (dd, J=8.9, 2.5 Hz, 1H), 7.59 (d, J=2.5 Hz, 1H), 7.73-7.78(m, 2H), 8.17 (s, 1H), 8.58 (s, 1H); ¹³C NMR (CDCl₃): δ 14.3, 61.9,65.5, 114.0, 114.5, 119.8, 125.3, 127.7, 129.8, 131.8, 132.3, 132.7,134.6, 139.6, 142.7, 154.1, 168.5, 186.9.

4-Bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetic acid. Preparedfrom ethyl 4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetate (31mg, 0.072 mmol) according to GP3 to give 28.4 mg (99%) white solid:LC/MS (an10p8): Rt 3.14 min, m/z 401; ¹H NMR (CDCl₃): δ 3.51 (s, 1H),4.80 (s, 1H), 6.97 (d, J=8.7 Hz, 1H), 7.38-7.44 (m, 1H), 7.49-7.55 (m,2H), 7.64-7.69 (m, 1H), 7.72-7.77 (m, 3H), 8.19 (s, 1H), 8.52 (s, 1H);¹³C NMR (CDCl₃): δ 67.2, 115.1, 116.6, 120.1, 124.5, 128.4, 130.0,131.9, 133.3, 136.2, 139.2, 143.3, 155.2, 169.9, 187.6.

INTERMEDIATE-2

Ethyl 2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetate. Prepared from(2-hydroxyphenyl)-(1-phenyl-1H-pyrazol-4-yl)ketone (264 mg, 1.0 mmol)and ethyl bromoacetate according to GP2 to give 235 mg (67%) of thetitle compound as white solid: ¹H NMR (CDCl₃): δ 1.26 (t, J=7.1 Hz, 3H),4.24 (q, J=7.1 Hz, 2H), 4.67 (s, 2H), 6.84 (d, J=8.3 Hz, 1H), 7.10 (ts,J=7.4, 0.8 Hz, 1 Hz), 7.29-7.36 (m, 1H), 7.41-7.53 (m, 4H), 7.72-7.78(m, 2H), 8.18 (s, 1H), 8.58 (s, 1H); ¹³C NMR (CDCl₃): δ 14.3, 61.7,65.4, 112.2, 118.8, 119.3, 119.7, 120.0, 122.1, 125.8, 127.6, 129.7,129.9, 130.1, 130.6, 131.8, 132.1, 136.3, 139.7, 142.8, 155.0, 168.9,188.7.

2-(1-Phenyl-1H-pyrazole-4-carbonyl)phenoxyacetic acid. Prepared fromethyl 2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetate according to GP3and purified by column chromatography (SiO₂, EtOAc:heptane, 1:1) to give15 mg (56%) of the title compound as white solid: LC/MS (an10n8): Rt2.90 min, m/z 321.0 [M−H]⁻; ¹H NMR (CDCl₃): δ 4.83 (s, 2H), 7.10 (d,J=8.3 Hz, 1H), 7.20 (t, J=7.5 Hz, 1H), 7.35-7.42 (m, 1H), 7.46-7.53 (m,2H), 7.54-7.61 (m, 1H), 7.66 (dd, J=7.5, 1.5 Hz, 1H), 7.70-7.75 (m, 2H);¹³C NMR (CDCl₃): δ 67.7, 115.5, 120.1, 122.8, 124.7, 128.3, 128.6,129.9, 131.0, 131.9, 134.0, 139.3, 143.5, 156.6, 170.4, 189.3.

INTERMEDIATE-3

Ethyl 4-fluoro-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetate.Prepared from 4-fluoro-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenol (282mg) and ethyl bromoacetate according to GP2 to give 335 mg (91%) yellowsolid: LC/MS (an10n8): Rt 3.16, m/z 339.0 [M−H]⁻; ¹H NMR (CDCl₃): δ 1.26(t, J=7.0 Hz, 3H), 4.23 (t, J=7.1 Hz, 2H), 4.63 (s, 2H), 6.81 (dd,J=9.0, 4.0 Hz, 1H), 7.13 (ddd, J=8.9, 4.5, 3.0 Hz, 1H), 7.21 (dd, J=8.1,3.2 Hz, 1H), 7.31-7.37 (m, 1H), 7.24-7.50 (m, 2H), 7.72-7.78 (m, 2H),8.18 (s, 1H), 8.58 (s, 1H); ¹³C NMR (CDCl₃): δ 14.3, 61.8, 66.1, 114.0(d, J_(CF)=7.6 Hz), 116.8 (d, J_(CF)=24.5 Hz), 118.3 (d, J_(CF)=23.5Hz), 119.7, 125.2, 127.7, 129.7, 131.8, 139.6, 142.8, 151.1 (d,J_(CF)=2.2 Hz), 157.6 (d, J_(CF)=241.1 Hz), 168.7, 187.1.

4-Fluoro-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetic acid. Preparedfrom ethyl 4-fluoro-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetate(31 mg) according to GP3 to give 30 mg (100%) of a pale yellow solid:LC/MS (an10n8): Rt 3.16, m/z 339.0 [M−H]⁻; ¹H NMR (CDCl₃): δ 4.60 (s,2H), 6.90 (dd, J=9.2 Hz, 1H), 7.08-7.17 (m, 1H), 7.21 (dd, J=7.9, 3.0Hz, 1H), 7.28-7.35 (m, 1H), 7.38-7.46 (m, 2H), 7.65 (d, J=7.5 Hz, 2H),8.06 (s, 1H), 8.44 (s, 1H).

INTERMEDIATE-4

4-Bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetonitrile.(5-Bromo-2-hydroxy-phenyl)-(1-phenyl-1H-pyrazol-4-yl)ketone (342 mg) wasadded bromoacetonitrile (122 mg), acetone (2 mL) and K₂CO₃ (140 mg), andthe reaction was stirred for 24 h. The reaction mixture was concentratedand the residue was partitioned between water and EtOAc. The organicphase was washed with brine, dried (MgSO4) and concentrated to give 383mg (100%) yellow solid, that was used directly in the next step: LC/MS(an10p8): Rt 4.39 min, m/z 381.5 [M+1]⁺; ¹H NMR (CDCl₃): δ 4.80 (s, 2H),7.07 (d, J=8.7 Hz, 1H), 7.35-7.42 (m, 1H), 7.45-7.54 (m, 2H), 7.60-7.69(m, 2H), 7.69-7.75 (m, 2H), 8.03 (s, 1H), 8.31 (s, 1H); ¹³C NMR (CDCl₃):δ 55.2, 114.7, 116.6, 116.7, 120.1, 125.1, 128.2, 129.9, 131.0, 132.6,133.2, 135.0, 139.3, 142.7, 153.0, 186.0.

[5-Bromo-2-(2H-tetrazol-5-ylmethoxy)phenyl](1-phenyl-1H-pyrazol-4-yl)ketone.[4-Bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]-acetonitrile (38mg) was added NaN3 (66 mg), ZnBr₂ (59 mg), isopropanol (1.3 mL) andwater (1.6 mL), and the reaction mixture was heated to reflux for 1 h.The mixture was added 3% HCl (1 mL) and EtOAc (4 mL) and stirred untiltwo clear phases appeared. The aqueous phase was added 3% HCl until pH<1and extracted with EtOAc. The combined organic phases were washed withbrine, dried (MgSO₄) and concentrated to give 47 mg white foam: LC/MS(an10n8): Rt 2.93, m/z 243.0 [M−H]⁻; ¹H NMR (CDCl₃): δ 5.69 (s, 2H),7.13 (d, J=8.6 Hz, 1H), 7.39-7.45 (m, 1H), 7.49-7.56 (m, 2H), 7.62-7.71(m, 2H), 7.71-7.79 (m, 1H), 8.13 (s, 1H), 8.45 (s, 1H); ¹³C NMR (CDCl₃):δ 63.3, 115.6, 117.7, 120.3, 124.5, 128.6, 130.0, 131.2, 132.0, 132.9,136.3, 139.1, 143.5, 154.7, 188.4.

3-(1-Phenyl-1H-pyrazole-4-carbonyl)biphenyl-4-yloxyacetic acid. Preparedfrom ethyl [4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetateand phenylboronic acid according to GP4: LC/MS (an10p8): Rt 1.05 min,m/z 398.6 [M−H]⁻; ¹H NMR (CDCl₃): δ 4.86 (s, 2H), 7.17 (d, J=8.6 Hz,1H), 7.35-7.57 (m, 8H), 7.70-7.75 (m, 2H), 7.78 (dd, J=8.6, 2.3 Hz, 1H),7.84 (d, J=2.3 Hz, 1H), 8.20 (s, 1H), 8.54 (s, 1H); ¹³C NMR (CDCl₃): δ67.7, 115.8, 120.1, 124.8, 127.1, 128.0, 128.3, 129.1, 129.3, 129.4,129.9, 132.3, 136.2, 139.3, 139.3, 143.5, 155.8, 170.4, 189.3.

INTERMEDIATE-5

(5-Bromo-2-hydroxyphenyl)-(1-pyridin-2-yl-1H-pyrazol-4-yl)ketone. To asuspension of 6-bromo-3-formylchromone (253 mg) in isopropanol (3 mL)and CH₂Cl₂ (2 mL) was added 2-hydrazinopyridine (109 mg), and themixture was stirred for 15 min to form a yellow slurry. The slurry wasadded KOH (0.25 g) in water (0.25 mL), and the reaction was heated toreflux for 1 h. The reaction mixture was diluted with water, added 3%HCl until pH<1 and extracted with CH₂Cl₂ (2×). The extract was washedwith water and brine, dried (MgSO₄) and concentrated to give 342 mgorange foam, which was purified by flash chromatography (SiO₂, EA:Hep,1:1) to give 53 mg (15%) yellow solid: LC/MS (an10p8): Rt 5.0 min, m/z343.5 [M+H]⁺; ¹H NMR (CDCl₃): δ 6.98 (d, J=8.9 Hz, 1H), 7.31 (ddd,J=7.3, 4.9, 0.9 Hz, 1H), 7.60 (dd, J=8.9, 2.5 Hz, 1H), 7.87-7.93 (m,1H), 8.03 (d, J=2.4 Hz, 1H), 8.04-8.09 (m, 1H), 8.02 (s, 1H), 8.47-8.51(m, 1H), 9.13 (s, 1H), 11.94 (s, 1H); ¹³C NMR (CDCl₃): δ 110.9, 113.3,120.8, 121.6, 122.8, 123.1, 130.5, 133.5, 138.9, 139.3, 143.3, 148.7,161.9, 191.4.

INTERMEDIATE-6

Ethyl 4-bromo-2-(1-pyridin-2-yl-1H-pyrazole-4-carbonyl)phenoxyacetate.Prepared from(5-bromo-2-hydroxyphenyl)-(1-pyridin-2-yl-1H-pyrazol-4-yl)ketone (43 mg)according to GP2 and purified by flash chromatography (SiO₂,EtOAc:heptane, 1:2) to give 34 mg (63%) of a pale yellow solid: LC/MS(an10p8): Rt 4.9 min, m/z 429.5 [M+H]⁺; ¹H NMR (CDCl₃): δ 1.23 (t, J=7.2Hz, 3H), 4.20 (q, J=7.2 Hz, 2H), 4.62 (s, 2H), 6.76 (d, J=8.6 Hz, 1H),7.23-7.28 (m, 1H), 7.53 (ddd, J=8.9, 2.6, 1.0 Hz, 1H), 7.58 (d, J=2.5Hz, 1H), 7.82-7.99 (m, 1H), 8.01 (d, J=8.1 Hz, 1H), 8.19 (s, 1H),8.40-8.44 (m, 1H), 8.99 (s, 1H); ¹³C NMR (CDCl₃): δ 14.3, 61.8, 66.1,114.5, 114.7, 131.6, 132.3, 132.4, 134.6, 139.1, 148.5, 154.4, 168.3,187.1.

4-Bromo-2-(1-pyridin-2-yl-1H-pyrazole-4-carbonyl)phenoxyacetic acid.Prepared fromethyl[4-bromo-2-(1-pyridin-2-yl-1H-pyrazole-4-carbonyl)phenoxy]-acetate(21 mg) according to GP3 to give 20 mg white foam: LC/MS (an10n8): Rt2.8 min, m/z 401.9 [M−H]⁻; ¹H NMR (CDCl₃): δ 4.79 (s, 2H), 6.98 (d,J=8.9 Hz, 1H), 7.28-7.34 (m, 1H), 7.67 (dd, J=8.9, 2.5 Hz, 1H), 7.75 (d,J=2.5 Hz, 1H), 7.86-7.94 (m, 1H), 8.02-8.08 (m, 1H), 8.22 (s, 1H), 8.43-8.48 (m, 1H), 9.04 (s, 1H).

INTERMEDIATE-7

(5-Bromo-2-hydroxy-phenyl)-[1-(4-methoxyphenyl)-1H-pyrazol-4-yl]ketone.To a suspension of 6-bromo-3-formylcromone (253 mg, 1.0 mmol) in ethanol(5 mL) was added 4-methoxyphenylhydrazine (175 mg, 1.0 mmol), and themixture was stirred under argon for 12 h an orange slurry. The slurrywas added KOH (260 mg) in water (0.25 mL), and the reaction was heatedto reflux for 1½ h. The reaction mixture was added 3% HCl until pH<1 andleft on ice to precipitate. The precipitate was filtered off and washedwith a small amount of cold ethanol to give 256 mg (69%) beige solidthat was used without further purification: LC/MS (an10p8): Rt 5.0 min,m/z 372.5 [M+H]⁺; ¹H NMR (CDCl₃): δ 3.88 (s, 3H), 6.98 (d, J=8.9 Hz,1H), 7.03 (d, J=9.1 Hz, 2H), 7.59 (dd, J=9.0, 2.5 Hz, 1H), 7.66 (d,J=9.1 Hz, 2H), 8.02 (d, J=2.4 Hz, 1H), 8.15 s, 1H), 8.39 (s, 1H), 11.92(s, 1H); ¹³C NMR (CDCl₃): δ 55.9, 110.9, 115.0, 120.8, 121.6, 121.8,122.9, 130.7, 133.5, 138.8, 142.3, 159.7, 161.8.

INTERMEDIATE-8

Ethyl4-bromo-2-[1-(4-methoxyphenyl)-1H-pyrazole-4-carbonyl]phenoxyacetate.Prepared from(5-bromo-2-hydroxyphenyl)-[1-(4-methoxyphenyl)-1H-pyrazol-4-yl]ketoneand ethyl bromoacetate according to GP2: LC/MS (an10p8): Rt 4.59 min,m/z 458.4/460.4 [M+H]⁺; ¹H NMR (CDCl₃): δ 1.26 (t, J=7.1 Hz, 3H), 3.84(s, 3H), 4.23 (q, J=7.1 Hz, 2H), 4.62 (s, 2H), 6.72 (d, J=8.9 Hz, 1H),6.97 (d, J=8.7 Hz, 2H), 7.52 (dd, J=8.9, 2.6 Hz, 1H), 7.58 (d, J=2.5 Hz,1H), 7.64 (d, J=8.9 Hz, 2H), 8.13 (s, 1H), 8.46 (s, 1H); ¹³C NMR(CDCl₃): δ 14.3, 55.8, 61.9, 65.6, 114.1, 114.4, 114.8, 121.4, 125.0,131.6, 132.4, 132.6, 133.2, 134.5, 142.5, 154.1, 159.2, 168.5, 186.9.

4-Bromo-2-[1-(4-methoxyphenyl)-1H-pyrazole-4-carbonyl]phenoxyaceticacid. Prepared from ethyl4-bromo-2-[1-(4-methoxy-phenyl)-1H-pyrazole-4-carbonyl]phenoxyacetate(23 mg) according to GP3 to give 21 mg (97%) white foam: LC/MS (an10n8):Rt 5.76 min, m/z 428.9 [M−H]⁻; ¹H NMR (CDCl₃): δ 3.86 (s, 3H), 4.77 (s,2H), 6.94 (d, J=8.9 Hz, 1H), 6.99 (d, J=9.2 Hz, 2H), 7.59-7.66 (m, 3H),7.71 (d, J=2.4 Hz, 1H), 8.14 (d, J=0.6 Hz, 1H), 8.40 (d, J=0.6 Hz,1H)¹³C NMR (CDCl₃): δ 55.9, 67.2, 115.0, 115.1, 116.6, 121.8, 124.2,130.7, 131.8, 132.7, 133.2, 136.1, 143.2, 155.2, 159.7, 169.9, 187.6.

[3′,5′-Difluoro-3-(1-phenyl-1H-pyrazole-4-carbonyl)biphenyl-4-yloxy]aceticacid. Preparedethyl[4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetate and3,5-difluorophenylboronic acid according to GP4: LC/MS (an10n8): Rt 3.03min, m/z 434.5 [M+H]⁺; ¹H NMR (CDCl₃): δ 4.85 (s, 2H), 6.81 (td, J=8.9,2.3 Hz, 1H), 7.07 (d, J=8.3 Hz, 2H), 7.14 (d, J=8.9 Hz, 1H), 7.41 (d,J=6.6 Hz, 1H), 7.48 (s, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.66-7.78 (m, 4H),8.23 (s, 1H), 8.57 (s, 1H)

[4′-Chloro-3-(1-phenyl-1H-pyrazole-4-carbonyl)biphenyl-4-yloxy]aceticacid. Prepared fromethyl[4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetate and4-chlorophenylboronic acid according to GP4: LC/MS (an10n8): Rt 3.08min, m/z 432.5 [M−H]⁻.

[4-Chloro-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetic acid.Prepared from(2-hydroxy-5-chlorophenyl)-(1-phenyl-1H-pyrazol-4-yl)-methanone andethyl bromoacetate according to GP2 and GP3: LC/MS (an10p8): Rt 3.08min, m/z 356.6 [M+1]⁺; ¹H NMR (CDCl₃): δ 4.75 (s, 2H), 6.95 (d, J=8.9Hz, 1H), 7.33-7.41 (m, 1H), 7.44-7.52 (m, 3H), 7.55 (d, J=2.6 Hz, 1H),7.69-7.75 (m, 2H), 8.18 (s, 1H), 8.52 (s, 1H).

[4-Methyl-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetic acid.Prepared from(2-hydroxy-5-methylphenyl)-(1-phenyl-1H-pyrazol-4-yl)-methanone andethyl bromoacetate according to GP2 and GP3: LC/MS (an10p8): Rt 3.08min, m/z 356.6 [M+1]⁺; ¹H NMR (CDCl₃): δ 2.37 (s, 3H), 4.78 (s, 2H),6.97 (d, J=9.0 Hz, 1H), 7.33-7.51 (m, 5H), 7.73 (d, J=6 Hz, 2H), 8.16(s, 1H), 8.51 (s, 1H), 11.21 (br s, 1H)

[4-Chloro-3-methyl-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]aceticacid. Prepared from(3-chloro-6-hydroxy-2-methyl-phenyl)-(1-phenyl-1H-pyrazol-4-yl)methanoneand ethyl bromoacetate according to GP2 and GP3: LC/MS (an10p8): Rt 3.34min, m/z 370.6 [M+1]⁺; ¹H NMR (CDCl₃): δ 2.44 (s, 3H), 4.77 (s, 2H),6.92 (s, 1H), 7.39 (d, J=9.0 Hz, 1H), 7.46-7.51 (m, 2H), 7.59 (s, 1H),7.72 (d, J=9.0 Hz, 2H), 8.19 (s, 1H), 8.52 (s, 1H), 10.39 (br s, 1H)

[2,4-Dichloro-6-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetic acid.Prepared from(3,5-dichloro-2-hydroxyphenyl)-(1-phenyl-1H-pyrazol-4-yl)methanone andethyl bromoacetate according to GP2 and GP3: LC/MS (an10p8): Rt 3.27min, m/z 390.5 [M+1]⁺; ¹H NMR (CDCl₃): δ 4.72 (s, 2H), 7.38-7.51 (m,4H), 7.57-7.58 (m, 1H), 7.70 (d, J=8.1 Hz, 2H), 8.06 (s, 1H), 8.36 (s,1H), 9.23 (br s, 1H).

4-Bromo-2-[1-(2-chloro-phenyl)-1H-pyrazole-4-carbonyl]phenoxyaceticacid. Prepared from 6-bromo-3-formylchromone, 2-chlorophenylhydrazineand ethyl bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8) Rt3.02 min, m/z 436.4 [M+H]⁺; ¹H NMR (CDCl₃): δ 4.76 (s, 2H), 6.94 (d,J=8.9 Hz, 1H), 7.39-7.47 (m, 2H), 7.53-7.67 (m, 3H), 7.74 (dd, J=2.4,0.9 Hz, 1H), 8.21 (s, 1H), 8.40 (s, 1H); ¹³C NMR (CDCl₃): δ 67.2, 115.0,116.7, 123.9, 127.9, 128.2, 128.7, 130.55, 130.59, 131.1, 133.3, 136.2,136.6, 137.1, 143.1, 155.2, 170.0, 187.5.

4-Bromo-2-[1-(3-chloro-phenyl)-1H-pyrazole-4-carbonyl]phenoxyaceticacid. Prepared from 6-bromo-3-formylchromone and 3-chlorophenylhydrazineaccording to: LC/MS (an10p8) Rt 3.57 min, m/z 436.4 [M+H]⁺; ¹H NMR(CDCl₃): δ 4.76 (s, 2H), 6.90 (d, J=8.9 Hz, 1H), 7.34 (dm, J=6.8 Hz,1H), 7.41 (t, J=8.3 Hz, 1H), 7.58-7.66 (m, 2H), 7.68 (d, J=2.0 Hz, 1H),7.78 (m, 1H), 8.17 (s, 1H), 8.51 (s, 1H); ¹³C NMR (CDCl₃): δ 66.8,115.1, 116.2, 117.9, 120.4, 124.9, 128.3, 130.7, 131.0, 132.0, 133.2,135.8, 136.1, 140.2, 143.4, 155.0, 170.1, 187.4.

4-Bromo-2-[1-(4-bromophenyl)-1H-pyrazole-4-carbonyl]phenoxyacetic acid.Prepared from 6-bromo-3-formylchromone, 4-bromophenylhydrazine and ethylbromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8) Rt 3.75 min,m/z 480.3 [M+H]⁺; ¹H NMR (CDCl₃): δ 4.75 (s, 2H), 6.89 (d, J=8.9 Hz,1H), 7.59-7.65 (m, 5H), 7.66-7.69 (m, 1H), 8.16 (s, 1H), 8.50 (s, 1H);¹³C NMR (CDCl₃): δ 66.5, 115.0, 115.9, 121.5, 121.8, 124.9, 130.8,131.8, 133.0, 133.1, 135.9, 138.2, 143.4, 154.8, 170.6, 187.4.

4-Bromo-2-[1-(4-chlorophenyl)-1H-pyrazole-4-carbonyl]phenoxyacetic acid.Prepared from 6-bromo-3-formylchromone, 4-chlorophenylhydrazine andethyl bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt3.53 min, m/z 436.4 [M+H]⁺; ¹H NMR (CDCl₃): δ 4.74 (s, 2H), 6.88 (d,J=8.9 Hz, 1H), 7.44 (d, J=8.5 Hz, 2H), 7.61 (dd, J=8.9, 2.4 Hz, 1H),7.63-7.70 (m, 3H), 8.17 (s, 1H), 8.49 (s, 1H); ¹³C NMR (CDCl₃): δ 66.4,114.9, 115.7, 121.2, 124.9, 130.0, 130.9, 131.9, 133.1, 133.9, 135.9,137.7, 143.3, 154.7, 170.8, 187.4.

4-Bromo-2-[1-(2-ethylphenyl)-1H-pyrazole-4-carbonyl]phenoxyacetic acid.Prepared from 6-bromo-3-formylchromone, 2-ethylphenylhydrazine and ethylbromoacetate according to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.58 min,427.0 m/z [M−H]⁺; ¹H NMR (CDCl₃): δ 1.14 (t, J=7.5 Hz, 3H), 2.58 (q,J=7.5, 2H), 4.76 (s, 2H), 6.93 (d, J=8.9 Hz, 1H), 7.28-7.34 (m, 2H),7.37-7.48 (m, 2H), 7.62 (dd, J=8.9, 2.6 Hz, 1H), 7.72 (d, J=2.5 Hz, 1H),8.15 (s, 1H), 8.18 (s, 1H).

4-Nitro-2-[1-(4-chlorophenyl)-1H-pyrazole-4-carbonyl]phenoxyacetic acid.Prepared from 6-nitro-3-formylchromone, 4-chlorophenylhydrazine andethyl bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt2.44 min, m/z 401.7 [M+H]⁺; ¹H NMR (CDCl₃): δ 4.84 (d, 2H), 7.1 (d,J=9.6 Hz, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.67 (d, J=8.1 Hz, 2H), 8.22 (s,1H), 8.36 (d, J=9.2 Hz, 1H), 8.41 (s, 1H), 8.53 (s, 1H); ¹³C NMR(CDCl₃): δ 65.6, 112.9, 121.3, 124.9, 126.2, 128.2, 130.0, 130.1, 131.9,134.1, 137.6, 142.4, 143.3, 159.7, 169.9, 186.2.

4-Nitro-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetic acid. Preparedfrom 6-nitro-3-formylchromone, 2-ethylphenylhydrazine and ethylbromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8) Rt 2.05 min,m/z 367.8 [M+H]⁺; ¹H NMR (CDCl₃): δ 4.83 (s, 2H), 7.01 (d, J=9.0 Hz,1H), 7.34-7.42 (m, 1H), 7.44-7.53 (m, 1H), 7.65-7.72 (m, 1H), 8.26 (s,1H), 8.34 (dd, J=9.0, 2.6 Hz, 1H), 8.41 (d, J=2.6 Hz, 1H), 8.53 (s, 1H).

4-Bromo-2-[1-(2-bromophenyl)-1H-pyrazole-4-carbonyl]phenoxyacetic acid.Prepared from 6-bromo-3-formylchromone, 2-bromophenylhydrazine and ethylbromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt 3.38 min,m/z 480.6 [M+H]⁺; ¹H NMR (CDCl₃): δ 4.75 (s, 2H), 6.91 (d, J=9.0 Hz,1H), 7.34-7.64 (m, 6H), 7.73-7.74 (m, 2H), 8.22 (s, 1H), 8.36 (s, 1H).

4-Bromo-2-[1-(2-fluorophenyl)-1H-pyrazole-4-carbonyl]phenoxyacetic acid.Prepared from 6-bromo-3-formylchromone, 2-fluorophenylhydrazine andethyl bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt3.36 min, m/z 418.7 [M+H]⁺; ¹H NMR (CDCl₃): δ 4.75 (s, 2H), 6.91 (d,J=8.9 Hz, 1H), 7.21-7.42 (m, 3H), 7.62 (dd, J=8.9, 2.4 Hz, 1H), 7.70 (d,J=2.5 Hz, 1H), 7.85-7.92 (m, 1H), 8.20 (s, 1H), 8.51 (d, J=2.3 Hz, 1H);¹³C NMR (CDCl₃): δ 66.9, 115.0, 116.3, 117.1, 117.4, 124.62, 124.63,125.0, 125.39, 125.44, 127.4, 127.5, 129.6, 129.7, 130.8, 133.2, 135.8,136.8, 143.0, 152.3, 155.0, 155.6, 170.5, 187.4.

4-Bromo-2-[1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carbonyl]phenoxyaceticacid. Prepared from 6-bromo-3-formylchromone,2-trifluoromethylphenylhydrazine and ethyl bromoacetate according toGP1, GP2 and GP3: LC/MS (an10p8): Rt 3.44 min, m/z 468.7 [M+H]⁺; ¹H NMR(CDCl₃): δ 4.72 (s, 2H), 6.89 (d, J=8.9 Hz, 1H), 7.53-7.75 (m, 5H), 7.84(d, J=7.9 Hz, 1H), 8.20 (s, 2H); ¹³C NMR (CDCl₃): δ 66.8, 114.9, 116.2,124.3, 126.3, 126.7, 127.58, 127.64, 129.2, 130.3. 130.7, 133.2, 136.0,136.9, 143.1, 155.0, 170.3, 187.4.

4-Bromo-2-[1-(3-bromophenyl)-1H-pyrazole-4-carbonyl]phenoxyacetic acid.Prepared from 6-bromo-3-formylchromone, 3-bromophenylhydrazine and ethylbromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt 4.29 min,m/z 480.5 [M+H]⁺; ¹H NMR (CDCl₃): δ 4.79 (s, 2H), 6.95 (d, J=9.0 Hz,1H), 7.28-7.40 (m, 1H), 7.53 (d, J=9 Hz, 1H), 7.65-7.73 (m, 3H), 7.96(s, 1H), 8.18 (s, 1H); 8.51 (s, 1H).

4-Bromo-2-[1-(3-trifluoromethylphenyl)-1H-pyrazole-4-carbonyl]phenoxyaceticacid. Prepared from 6-bromo-3-formylchromone,3-trifluoromethylphenylhydrazine and ethyl bromoacetate according toGP1, GP2 and GP3: LC/MS (an10p8): Rt 4.54 min, m/z 468.7 [M+H]⁺; ¹H NMR(CDCl₃): δ 4.76 (s, 2H), 6.89 (d, J=8.9 Hz, 1H), 7.57-7.66 (m, 3H), 7.68(d, J=2.4 Hz, 1H), 7.89-7.96 (m, 1H), 8.04 (s, 1H), 8.20 (s, 1H), 8.59(s, 1H), 9.15 (br s, 1H).

4-Bromo-2-[1-(2,4-dichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxyaceticacid. Prepared from 6-bromo-3-formylchromone,2,4-dichlorophenylhydrazine and ethyl bromoacetate according to GP1, GP2and GP3: LC/MS (an10p8): Rt 4.35 min, m/z 468.6 [M+H]⁺; ¹H NMR(DMSO-d₆): δ 4.76 (s, 2H), 7.03 (d, J=9.0 Hz, 1H), 7.52 (m, 1H),7.57-7.69 (m, 3H), 7.89 (m, 1H), 8.19 (s, 1H), 8.69 (s, 1H); ¹³C NMR(DMSO-d₆): δ 55.8, 103.6, 106.2, 115.2, 119.5, 120.6, 120.7, 121.1,122.4, 125.5, 125.6, 127.1, 128.3, 133.4, 145.1, 160.9, 177.4.

4-Nitro-2-[1-(2-chlorophenyl)-1H-pyrazole-4-carbonyl]phenoxyacetic acid.Prepared from 6-nitro-3-formylchromone 2-chlorophenylhydrazine and ethylbromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt 2.42 min,m/z 401.8 [M+H]⁺; ¹H NMR (CDCl₃): δ 4.83 (s, 2H), 7.01 (d, J=9.0 Hz,2H), 7.42-7.48 (m, 2H), 7.56-7.63 (m, 2H), 8.34-8.40 (m, 2H), 8.5 (s,2H).

4-Nitro-2-[1-(2-bromophenyl)-1H-pyrazole-4-carbonyl]phenoxyacetic acid.Prepared from 6-nitro-3-formylchromone, 2-bromophenylhydrazine and ethylbromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt 2.33 min,m/z 445.9 [M−H]⁺; ¹H NMR (CDCl₃): δ 4.85 (s, 2H), 7.04 (d, J=9 Hz, 1H),7.37-7.81 (m, 4H), 8.32-8.44 (m, 3H), 8.50 (s, 1H).

4-Bromo-2-[1-(2,6-dichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxyaceticacid. Prepared from 6-bromo-3-formylchromone,2,6-dichlorophenylhydrazine and ethyl bromoacetate according to GP1, GP2and GP3: LC/MS (an10p8): Rt 2.56 min, m/z 468.6 [M+H]⁺; ¹H NMR (CDCl₃):δ 4.72, 6.88 (d, J=8.9 Hz, 1H), 7.37-7.44 (m, 1H), 7.45-7.52 (m, 2H),7.59 (d, J=8.7 Hz, 1H), 7.70 (m, 1H), 8.14 (s, 1H), 8.26 (s, 1H).

4-Ethyl-2-[1-(2-bromophenyl)-1H-pyrazole-4-carbonyl]phenoxyacetic acid.Prepared from 6-ethyl-3-formylchromone, 2-bromophenylhydrazine and ethylbromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt 2.88 min,m/z 428.8 [M+H]⁺.

2-[1-(2-Chlorophenyl)-1H-pyrazole-4-carbonyl]-4-isopropylphenoxyaceticacid. Prepared from 6-isopropyl-3-formylchromone,2-chlorophenylhydrazine and ethyl bromoacetate according to GP1, GP2 andGP3: LC/MS (an10p8): Rt 2.83 min, m/z 398.8 [M+H]⁺; ¹H NMR (CDCl₃): δ1.28 (d, J=7.0 Hz, 6H), 2.93 (septet, J=6.9 Hz, 1H), 4.82 (s, 2H), 7.04(d, J=8.5 Hz, 1H), 7.40-7.65 (m, 6H), 8.28 (s, 1H), 8.40 (s, 1H).

{4-Bromo-2-[1-(4-trifluoromethoxyphenyl)-1H-pyrazole-4-carbonyl]phenoxyaceticacid. Prepared from 6-bromo-3-formylchromone,4-trifluoromethoxyphenylhydrazine and ethyl bromoacetate according toGP1, GP2 and GP3: LC/MS (an10p8): Rt 3.24 min, m/z 484.6 [M+H]⁺; ¹H NMR(CDCl₃): δ 4.75 (s, 2H), 6.89 (d, J=8.9 Hz, 1H), 7.34 (d, J=9.0 Hz, 2H),7.61 (dd, J=8.9, 2.6 Hz, 1H), 7.67 (m, 1H), 7.72-7.80 (m, 2H), 8.17 (s,1H), 8.51 (s, 1H); ¹³C NMR (CDCl₃): δ 66.5, 115.0, 115.8, 121.4, 122.5,125.0, 130.8, 132.0, 133.1, 136.0, 137.6, 143.4, 148.6, 148.7, 154.8,170.8, 187.4.

4-Bromo-2-[1-(2,4-dibromophenyl)-1H-pyrazole-4-carbonyl]phenoxyaceticacid. Prepared from 6-bromo-3-formylchromone, 2,4-dibromophenylhydrazineaccording and ethyl bromoacetate to GP1, GP2 and GP3: LC/MS (an10p8): Rt3.41 min, m/z 556.4 [M+H]⁺; ¹H NMR (CDCl₃): δ 4.75 (s, 2H), 6.92 (d,J=9.0 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.63 (m, 2H), 7.73 (d, J=2.5 Hz,1H), 7.92 (d, J=2.1 Hz, 1H), 8.22 (s, 1H), 8.37 (s, 1H).

4-Bromo-2-[1-(4-bromo-2-chlorophenyl)-1H-pyrazole-4-carbonyl]phenoxyaceticacid. Prepared from 6-bromo-3-formylchromone,4-bromo-2-chlorophenylhydrazine and ethyl bromoacetate according to GP1,GP2 and GP3: LC/MS (an10p8): Rt 3.34 min, m/z 512.5 [M+H]⁺; ¹H NMR(CDCl₃): δ 4.78 (s, 2H), 6.95 (d, J=8.6 Hz, 1H), 7.51-7.76 (m, 5H), 8.21(s, 1H), 8.42 (s, 1H).

4-Bromo-2-[1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxyaceticacid. Prepared from 6-bromo-3-formylchromone,2,4,6-trichlorophenylhydrazine and ethyl bromoacetate according to GP1,GP2 and GP3: LC/MS (an10p8): Rt 3.35 min, m/z 502.6 [M+H]⁺; ¹H NMR(CDCl₃): δ 4.91 (s, 2H), 7.05 (d, J=8.9 Hz, 1H), 7.68 (s, 2H), 7.78 (d,J=8.5 Hz, 1H), 7.88 (s, 1H), 8.31 (s, 1H), 8.43 (s, 1H), 9.03 (br s,1H).

4-Methoxy-2-[1-phenyl-1H-pyrazole-4-carbonyl]phenoxyacetic acid.Prepared from 6-bromo-3-formylchromone, 2,4-dichlorophenylhydrazine andethyl bromoacetate according to GP1, GP2 and GP3: LC/MS (an10n8): Rt2.46 min, m/z 350.9 [M−H]⁺; ¹H NMR (CDCl₃): δ 3.81 (s, 3H), 4.77 (s,2H), 7.02-7.16 (m, 3H), 7.41 (d, J=7.5 Hz, 1H), 7.50 (t, J=8.1 Hz, 2H),7.73 (d, J=8.5 Hz, 2H), 8.17 (s, 1H), 8.52 (s, 1H).

2-[4-Bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]propionic acid.Prepared from (5-bromo-2-hydroxyphenyl)-(1-phenyl-1H-pyrazol-4-yl)ketoneand ethyl 2-bromopropionate according to GP2 and GP3: LC/MS (an10p8) Rt2.51 min, m/z 415 [M+H]⁺; ¹H NMR (CDCl₃): δ 1.65 (d, J=6.8 Hz, 3H), 4.93(q, J=6.8 Hz, 1H), 6.96 (d, J=8.9 Hz, 1H), 7.35-7.43 (m, 1H), 7.46-7.53(m, 2H), 7.62 (dd, J=8.9, 2.5 Hz, 1H), 7.70-7.76 (m, 3H), 8.17 (s, 1H),8.52 (s, 1H); ¹³C NMR (CDCl₃): δ 18.8, 75.2, 114.8, 116.7, 120.1, 124.4,128.3, 130.0, 133.3, 136.2, 139.2, 143.3, 155.0, 173.1, 187.8.

2(S)-[4-Bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)-phenoxy]-propionicacid. (5-Bromo-2-hydroxyphenyl)-(1-phenyl-1H-pyrazol-4-yl)ketone (100mg, 0.29 mmol), (R)-(+)-bromoacetic acid (44 mg, 0.29 mmol) ethyl2-bromopropionate and K2CO3 (80 mg, 0.58 mmol) in acetone was stirred atroom temperature for 16 h. The reaction mixture was concentrated and theresidue was partitioned between EtOAc and dilute HCl (pH˜1). The organicphase was dried (Na₂SO₄) and concentrated, and the residue was purifiedby flash chromatography (EtOAc:heptane, 1:1) to yield 55 mg (46%) of thetitle compound: Chiral HPLC (Column: Ciracel OD (0.46 cm×24 cm); Eluent:isocratic, 85% hexane+15% 2-propanol+0.1% TFA; Flow 0.5 mL/min) Rt 15.7min, >90% e.e. (Racemic material eluates with baseline separation ofenantiomeres: Rt 15.7 and 16.7 min.) MS and NMR spectra correspond toracemic material.

2-{4-Bromo-2-[1-(2-chlorophenyl)-1-H-pyrazole-4-carbonyl]phenoxy}propionicacid. Prepared from 6-bromo-3-formylchromone, 2-chlorophenylhydrazineand ethyl 2-bromopropionate according to GP1, GP2 and GP3: LC/MS(an10n8): Rt 2.56 min, 448.9 m/z [M−H]⁺; ¹H NMR (CDCl₃): δ 1.65 (d,J=7.0 Hz, 3H), 4.93 (q, J=7.0 Hz, 1H), 6.96 (d, J=8.9 Hz, 1H), 7.41-7.47(m, 2H), 7.55-7.64 (m, 3H), 7.74 (s, 1H), 8.23 (s, 1H), 8.42 (s, 1H);¹³C NMR (CDCl₃): δ 18.9, 75.4, 115.0, 117.0, 124.1, 128.1, 128.4, 128.9,130.7, 131.3, 133.6, 136.4, 136.8, 137.3, 143.3, 155.2, 173.5, 188.0.

2-{4-Bromo-2-[1-(2,6-dichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid. Prepared from 6-bromo-3-formylchromone,2,6-dichlorophenylhydrazine and ethyl 2-bromopropionate according toGP1, GP2 and GP3: LC/MS (an10n8): Rt 2.55 min, 482.9 m/z [M−H]⁺; ¹H NMR(CDCl₃): δ 1.65 (d, J=6.8 Hz, 3H), 4.91 (q, J=6.8 Hz, 1H), 6.93 (d,J=8.9 Hz, 1H), 7.41-7.53 (m, 3H), 7.62 (dd, J=8.9, 2.5 Hz, 1H), 7.74 (d,J=2.4, 1H), 8.17 (s, 1H), 8.28 (s, 1H); ¹³C NMR (CDCl₃): δ 18.9, 75.1,114.9, 116.8, 124.2, 129.3, 130.7, 132.0, 133.6, 134.5, 135.6, 136.4,137.6, 143.6, 155.1, 173.6, 187.8.

{4-Bromo-2-[1-(2-cyano-phenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid. Prepared from 6-bromo-3-formylchromone, 2-hydrazinobenzonitril(prepared according to van der Mey, et al. J. Med. Chem. 2003,2008-2016) and ethyl bromoacetate according to GP1, GP2 and GP3: ¹H NMR(DMSO-d₆): δ 4.72 (s, 2H), 7.17 (d, J=8.9 Hz, 1H), 7.36 (t, J=15.1, 7.3Hz, 1H), 7.8 (m, 4H), 8.29 (d, J=8.3 Hz, 1H), 9.03 (s, 1H), 9.66 (s,1H), 13.04 (br s, 1H).

{4-Bromo-2-[1-(2-ethoxyphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid. Prepared from 6-bromo-3-formylchromone, 2-ethoxyphenylhydrazineand ethyl 2-bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8):Rt 2.33 min, m/z 446.7 [M+H]⁺; ¹H NMR (CDCl₃): δ 1.47 (t, J=7.0 Hz, 3H),4.18 (q, J=7.0 Hz, 2H), 4.78 (s, 2H), 6.97 (d, J=8.9 Hz, 1H), 7.09 (d,J=8.7 Hz, 2H), 7.36 (td, J=7.9, 1.8 Hz, 1H), 7.64 (dd, J=8.9, 2.5 Hz,1H), 7.79 (d, J=2.5 Hz, 1H), 7.80 (dd, J=7.9, 1.6 Hz, 1H), 8.22 (s, 1H),8.65 (s, 1H).

{4-Bromo-2-[1-(4-bromo-2-ethylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid. Prepared from 6-bromo-3-formylchromone,4-bromo-2-ethylphenylhydrazine and ethyl bromoacetate according to GP1,GP2 and GP3: LC/MS (an10n8): Rt 2.78 min, m/z 506.6 [M−H]⁻; ¹H NMR(CDCl₃): δ 1.16 (td, J=7.8, 2.4 Hz, 3H), 2.58 (qd, J=7.8, 1.8 Hz, 2H),4.77 (s, 2H), 6.94 (d, J=9.0 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 7.47 (d,J=8.5 Hz, 1H), 7.56 (s, 1H), 7.65 (d, J=8.7 Hz, 1H), 7.72 (s,1H), 8.15(s, 1H), 8.19 (s, 1H).

{4-Bromo-2-[1-(2-phenoxyphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid. Prepared from 6-bromo-3-formylchromone,4-bromo-2-ethylphenylhydrazine and ethyl bromoacetate according to GP1,GP2 and GP3: LC/MS (an10n8): Rt 2.77 min, m/z 492.7 [M−H]⁻; ¹H NMR(CDCl₃): δ 4.75 (s, 2H), 6.95 (d, J=8.6 Hz, 1H), 7.00-7.09 (m, 3H), 7.15(t, J=7.5 Hz, 1H), 7.29-7.40 (m, 4H), 7.62-7.68 (m, 2H), 7.90 (d, J=9.0Hz, 1H), 8.17 (s, 1H), 8.60 (s, 1H).

{4-Bromo-2-[1-(2-methylthiophenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid. Prepared from 6-bromo-3-formylchromone,2-methylthiophenylhydrazine and ethyl bromoacetate according to GP1, GP2and GP3: LC/MS (an10n8): Rt 2.26 min, m/z 446.7 [M−H]⁻; ¹H NMR (CDCl₃):δ 2.46 (s, 3H), 4.77 (s, 2H), 6.93 (d, J=8.9 Hz, 1H), 7.28-7.32 (m, 1H),7.39-7.49 (m, 3H), 7.62 (dd, J=9.0, 2.5 Hz, 1H), 7.76 (s, 1H), 8.23 (s,1H), 8.31 (s, 1H).

{4-Bromo-2-[1-(2-bromo-4-methylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid. Prepared from 6-bromo-3-formylchromone,2-bromo-4-methylphenylhydrazine and ethyl bromoacetate according to GP1,GP2 and GP3: LC/MS (an10n8): Rt 2.47 min, m/z 492.6 [M−H]⁻; ¹H NMR(CDCl₃): δ 2.44 (s, 3H), 4.80 (s, 2H), 6.99 (d, J=8.9 Hz, 1H), 7.27-7.30(m, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.58 (s, 1H), 7.67 (d, J=9.0 Hz, 1H),7.80 (s, 1H), 8.20 (s, 1H), 8.33 (s, 1H).

2-{4-Bromo-2-[1-(4-bromo-2-ethylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid. Prepared from 6-bromo-3-formylchromone,4-bromo-2-ethylphenylhydrazine and ethyl bromoacetate according to GP1,GP2 and GP3: LC/MS (an10p8): Rt 2.72 min, m/z 522.6 [M+H]⁺; ¹H NMR(CDCl₃): δ 1.16 (t, J=7.7 Hz, 3H), 1.67 (d, J=6.8 Hz, 3H), 2.59 (q,J=7.5 Hz, 2H), 4.95 (q, J=7.0 Hz,1H), 6.96 (d, J=9.0 Hz, 1H), 7.21 (d,J=8.3 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.55 (s, 1H), 7.63 (d, J=9.0 Hz,1H), 7.73 (s, 1H), 8.17 (s, 1H), 8.18 (s, 1H).

2-{4-Bromo-2-[1-(2-phenoxyphenyl)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid. Prepared from 6-bromo-3-formylchromone, 2-phenoxyphenylhydrazineand ethyl 2-bromopropionate according to GP1, GP2 and GP3: LC/MS(an10p8): Rt 2.68 min, m/z 508.7 [M+H]⁺; ¹H NMR (CDCl₃): δ 1.65 (d,J=6.8 Hz, 3H), 4.92 (q, J=7.3 Hz,1H), 6.96-7.18 (m, 5H), 7.26-7.39 (m,4H), 7.62 (d, J=8.6 Hz, 1H), 7.67 (s, 1H), 7.90 (d, J=7.5 Hz, 1H), 8.17(s, 1H), 8.61 (s, 1H).

2-{4-Bromo-2-[1-(2-ethoxyphenyl)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid. Prepared from 6-bromo-3-formylchromone, 2-ethoxyphenylhydrazineand ethyl 2-bromopropionate according to GP1, GP2 and GP3: LC/MS(an10p8): Rt 2.39 min, m/z 458.7 [M+H]⁺; ¹H NMR (CDCl₃): δ 1.49 (t,J=7.1 Hz, 3H), 1.86 (d, J=7.1 Hz, 3H), 4.19 (m,2H), 4.98 (q, J=6.9 Hz,1H), 7.02-7.12 (m,3H), 7.37 (t, J=8.2 Hz, 1H), 7.66 (d, J=8.9 Hz, 1H),7.78 (s, 1H), 7.83 (d, J=7.9 Hz, 1H), 8.20 (s, 1H), 8.67 (s, 1H).

2-{4-Bromo-2-[1-(2-methylthio)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid. Prepared from 6-bromo-3-formylchromone, 2-ethoxyphenylhydrazineand ethyl 2-bromopropionate according to GP1, GP2 and GP3: LC/MS(an10n8): Rt 2.56 min, 460.9 m/z [M−H]⁺; ¹H NMR (CDCl₃): δ 1.71 (d,J=6.8 Hz, 3H), 2.46 (s, 3H), 4.96 (q, J=7.0 Hz, 1H), 7.00 (d, J=8.9 Hz,1H), 7.29-7.34 (m, 1H), 7.40-7.50 (m, 3H), 7.64 (dd, J=8.9, 2.5 Hz, 1H),7.80 (s, 1H), 8.22 (s, 1H), 8.32 (s, 1H).

2-{4-Bromo-2-[1-(2-bromo-4-methylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid. Prepared from 6-bromo-3-formylchromone,2-bromo-4-methylphenylhydrazine and ethyl 2-bromopropionate according toGP1, GP2 and GP3: LC/MS (an10n8): Rt 2.74 min, 506.8 m/z [M−H]⁺; ¹H NMR(CDCl₃): δ 1.72 (d, J=7.0 Hz, 3H), 2.45 (s, 3H), 4.98 (q, J=7.0 Hz, 1H),7.03 (d, J=8.9 Hz, 1H), 7.28-7.30 (m, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.59(s, 1H), 7.67 (dd, J=8.9, 2.43 Hz, 1H), 7.81 (d, J=2.6 Hz, 1H), 8.19 (s,1H), 8.34 (s, 1H).

2-{4-Bromo-2-[1-(2,4-dichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid. Prepared from 6-bromo-3-formylchromone,2,4-dichlorophenylhydrazine and ethyl 2-bromopropionate according toGP1, GP2 and GP3: LC/MS (an10n8): Rt 2.83 min, 482.8 m/z [M−H]⁺; ¹H NMR(CDCl₃): δ 1.50 (d, J=6.0 Hz, 3H), 4.75 (q, J=4.5 Hz, 1H), 6.88 (d,J=8.5 Hz, 1H), 7.40 (dd, J=8.5, 1.9 Hz, 1H), 7.50 (d, J=7.5 Hz, 1H),7.54-7.57 (m, 2H), 7.61 (s, 1H), 8.16 (s, 1H), 8.32 (s, 1H).

{4-Bromo-2-[1-(2-trifluoromethoxyphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid. Prepared from 6-bromo-3-formylchromone,2-trifluoromethoxyphenylhydrazine and ethyl bromoacetate according toGP1, GP2 and GP3: LC/MS (an10n8): Rt 2.43 min, m/z 482.7 [M−H]⁻; ¹H NMR(CDCl₃): δ 4.77 (s, 2H), 6.95 (d, J=8.6 Hz, 1H), 7.45-7.50 (m, 3H), 7.65(dd, J=8.9, 2.5 Hz, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.82 (s, 1H), 8.23 (s,1H), 8.40 (s, 1H).

{2-[1-(2,6-Dichlorophenyl)-1H-pyrazole-4-carbonyl]-4-ethylphenoxy}aceticacid. Prepared from 6-ethyl-3-formylchromone,2,6-dichlorophenylhydrazine and ethyl bromoacetate according to GP1, GP2and GP3: LC/MS (an10n8): Rt 2.25 min, m/z 416.8 [M−H]⁻; ¹H NMR (CDCl₃):δ 1.26 (t, J=7.5 Hz, 3H), 2.69 (q, J=7.7 Hz, 2H), 4.82 (s, 2H), 7.04 (d,J=8.7 Hz, 1H), 7.39-7.44 (m, 1H), 7.46-7.54 (m, 4H), 8.14 (s, 1H), 8.25(s, 1H).

{4-Bromo-2-[1-(2,4-dimethylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid. Prepared from 6-bromo-3-formylchromone,2,4-dimethylphenylhydrazine and ethyl bromoacetate according to GP1, GP2and GP3: LC/MS (an10n8): Rt 2.41 min, m/z 428.7 [M−H]⁻; ¹H NMR (CDCl₃):δ 2.26 (s, 3H), 2.40 (s, 3H), 4.75 (s, 2H), 6.91 (d, J=8.9 Hz, 1H), 7.11(d, J=8.1 Hz, 1H), 7.17 (s, 1H), 7.23 (d, J=8.1 Hz, 1H), 7.60 (dd,J=8.9, 2.46 Hz, 1H), 7.71 (s, 1H), 8.15 (s, 1H), 8.22 (s, 1H).

2-{4-Bromo-2-[1-(2,4-dimethylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid. Prepared from 6-bromo-3-formylchromon, 2,4-dimethylphenylhydrazineand ethyl 2-bromopropionate according to GP1, GP2 and GP3: LC/MS(an10n8): Rt 2.40 min, m/z 442.7 [M−H]⁻; ¹H NMR (CDCl₃): δ 1.67 (d,J=6.9 Hz, 3H), 2.25 (s, 3H), 2.40 (s, 3H), 4.93 (q, J=6.8 Hz, 1H), 6.97(d, J=8.9 Hz, 1H), 7.12 (d, J=8.1 Hz, 1H), 7.17 (s, 1H), 7.25 (d, J=8.1Hz, 1H), 7.62 (dd, J=8.7, 1.52 Hz, 1H), 7.73 (s, 1H), 8.15-8.16 (m, 2H).

[2-(1-Benzyl-1H-pyrazole-4-carbonyl)-4-bromophenoxy]acetic acid.Prepared from 6-bromo-3-formylchromone, benzylhydrazine and ethylbromoacetate according to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.14 min,m/z 414.7 [M−H]⁻; ¹H NMR (CDCl₃): δ 4.70 (s, 2H), 5.36 (s, 2H), 6.88 (d,J=8.7 Hz, 1H), 7.28-7.30 (m, 2H), 7.40-7.46 (m, 3H), 7.57 (d, J=8.9 Hz,1H), 7.63 (s, 1H), 8.01 (s, 1H), 8.04 (s, 1H).

2-[2-(1-Benzyl-1H-pyrazole-4-carbonyl)-4-bromophenoxy]propionic acid.Prepared from 6-bromo-3-formylchromone, benzylhydrazine and ethyl2-bromopropionate according to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.16min, m/z 428.8 [M−H]⁻; ¹H NMR (CDCl₃): δ 1.59 (d, J=6.8 Hz, 3H), 4.88(q, J=7.1 Hz, 1H), 5.35 (s, 2H), 6.91 (d, J=8.9 Hz, 1H), 7.30-7.42 (m,5H), 7.53-7.71 (m, 2H), 8.01 (s, 2H).

{4-Bromo-2-[1-(4-chloro-2-methylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid. Prepared from 6-bromo-3-formylchromone,4-chloro-2-methylphenylhydrazine and ethyl bromoacetate according toGP1, GP2 and GP3: LC/MS (an10n8): Rt 2.49 min, m/z 448.7 [M−H]⁻; ¹H NMR(CDCl₃): δ 2.27 (s, 3H), 4.75 (s, 2H), 6.91 (d, J=8.9 Hz, 1H), 7.31 (s,2H), 7.36 (s, 1H), 7.63 (d, J=8.7 Hz, 1H), 7.70 (s, 1H), 8.17 (s, 1H),8.21 (s, 1H).

{4-Bromo-2-[1-(2,5-dichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid. Prepared from 6-bromo-3-formylchromone,2,5-dichlorophenylhydrazine and ethyl bromoacetate according to GP1, GP2and GP3: LC/MS (an10n8): Rt 2.46 min, m/z 468.6 [M−H]⁻; ¹H NMR (CDCl₃):δ 4.78 (s, 2H), 6.92 (d, J=8.9 Hz, 1H), 7.39 (dd, J=8.7, 2.44 Hz, 1H),7.50 (d, J=8.7 Hz, 1H), 7.61 (dd, J=8.9, 2.53 Hz, 1H), 7.70 (dd, J=8.1,2.36 Hz, 2H), 8.22 (s, 1H), 8.45 (s, 1H).

{4-Bromo-2-[1-(2-methoxyphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid. Prepared from 6-bromo-3-formylchromone, 2-methylphenylhydrazineand ethyl bromoacetate according to GP1, GP2 and GP3: LC/MS (an10n8): Rt2.20 min, m/z 430.7 [M−H]⁻; ¹H NMR (CDCl₃): δ 3.96 (s,3H), 4.79 (s, 2H),6.96 (d, J=8.9 Hz, 1H), 7.11 (t, J=8.2 Hz, 2H), 7.40 (t.d, J=8.1, 1.5Hz, 1H), 7.65 (dd, J=8.9, 2.5 Hz, 1H), 7.76 (d, J=2.5 Hz, 2H), 8.18 (s,1H), 8.60 (s, 1H).

{4-Bromo-2-[1-(3,4-dichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid. Prepared from 6-bromo-3-formylchromone, 3,4-chlorophenylhydrazineand ethyl bromoacetate according to GP1, GP2 and GP3: LC/MS (an10n8): Rt2.77 min, m/z 468.6 [M−H]⁻; ¹H NMR (CDCl₃): δ 4.78 (s, 2H), 6.90 (d,J=8.7 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.64 (d, J=8.9 Hz, 1H), 7.69 (d,J=2.43 Hz, 2H), 7.91 (d, J=2.46 Hz, 1H), 8.18 (s, 1H), 8.53 (s, 1H).

2-{4-Bromo-2-[1-(4-chloro-2-methylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid. Prepared from 6-bromo-3-formylchromone,4-chloro-2-methylphenylhydrazine and ethyl 2-bromopropionate accordingto GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.55 min, m/z 462.7 [M−H]⁻; ¹HNMR (CDCl₃): δ 1.65 (d, J=6.9 Hz, 3H), 2.28 (s, 3H), 4.92 (d, J=6.8 Hz,1H), 6.95 (d, J=8.9 Hz, 1H), 7.30 (s, 2H), 7.37 (s, 1H), 7.63 (d, J=8.9Hz, 1H), 7.72 (s, 1H), 8.19 (s, 2H).

2-{4-Bromo-2-[1-(2,5-dichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid. Prepared from 6-bromo-3-formylchromone,2,5-dichlorophenylhydrazine and ethyl 2-bromopropionate according toGP1, GP2 and GP3: LC/MS (an10n8): Rt 2.51 min, m/z 482.6 [M−H]⁻; ¹H NMR(CDCl₃): δ 1.70 (d, J=6.8 Hz, 3H), 4.90 (q, J=6.9 Hz, 1H), 6.93 (d,J=9.1 Hz, 1H), 7.40 (dd, J=8.7, 2.5 Hz, 1H), 7.50 (d, J=8.6 Hz, 1H),7.62 (dd, J=8.9, 2.5 Hz, 1H), 7.68 (d, J=2.3 Hz, 1H), 7.71 (d, J=2.4 Hz,1H), 8.22 (s, 1H) 8.45 (s, 1H).

2-{4-Bromo-2-[1-(3,4-dichloro-phenyl)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid. Prepared from 6-bromo-3-formylchromon, 3,4-dichlorophenylhydrazineand ethyl 2-bromopropionate according to GP1, GP2 and GP3: LC/MS(an10n8): Rt 2.83 min, m/z 482.6 [M−H]⁻; ¹H NMR (CDCl₃): δ 1.63 (d,J=6.8 Hz, 3H), 4.93 (q, J=6.9 Hz, 1H), 6.92 (d, J=9.03 Hz, 1H),7.55-7.65 (m, 3H), 7.70 (s,1H), 7.93 (d, J=2.25 Hz, 1H), 8.20 (s, 1H),8.57 (s, 1H).

2-{4-Bromo-2-[1-(2-methoxyphenyl)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid. Prepared from 6-ethyl-3-formylchromone,2,6-dichlorophenylhydrazine and ethyl 2-bromopropionate according toGP1, GP2 and GP3: LC/MS (an10n8): Rt 2.23 min, m/z 444.7 [M−H]⁻; ¹H NMR(CDCl₃): δ 1.68 (d, J=7.0 Hz, 3H), 3.95 (s, 3H), 4.95 (d, J=7.0 Hz, 1H),6.99 (d, J=8.7 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 7.14 (s, 1H), 7.37-7.43(m,1H), 7.63 (dd, J=8.9, 2.6 Hz, 1H), 7.77 (s, 1H), 7.79 (s,1H), 8.19(s, 1H), 8.62 (s, 1H).

[4-Amino-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetic acid. Amixture of ethyl 4-nitro-2-(phenyl-1H-pyrazole-4-carbonyl)phenoxyacetate(190 mg, 0.48 mmol) and 10% Pd/C (100 mg) in MeOH (50 mL) was stirredunder an atmosphere of hydrogen of 12 h, then filtered through a pad ofcelite and concentrated, and the product was hydrolyzed according to GP3to give the title compound.

{4-Bromo-2-[1-(4-bromo-2-chlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid. Prepared from 6-bromo-3-formylchromone,4-bromo-2-chlorophenylhydrazine and ethyl bromoacetate according to GP1,GP2 and GP3: LC/MS (an10n8): Rt 2.57 min, m/z 526.6 [M−H]⁻; ¹H NMR(DMSO): δ 1.31 (d, J=6.8 Hz, 3H), 4.94 (q, J=6.6 Hz, 1H), 6.92 (d, J=8.9Hz, 1H), 7.53 (d, J=2.5 Hz, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.66 (dd,J=9.0, 2.5 Hz, 1H), 7.76 (dd, J=8.5, 2.3 Hz, 1H), 8.04 (d, J=2.1 Hz,1H), 8.22 (s, 1H), 8.77 (s, 1H).

2-{4-Bromo-2-[1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid. Prepared from 6-bromo-3-formylchromone,2,4,6-trichlorophenylhydrazine and ethyl 2-bromopropionate according toGP1, GP2 and GP3: LC/MS (an10n8): Rt 2.61 min, m/z 516.6 [M−H]⁺; ¹H NMR(DMSO): δ 1.33 (d, J=6.8 Hz, 3H), 4.94 (q, J=7.0 Hz, 1H), 6.92 (d, J=9.2Hz, 1H), 7.54 (d, J=2.4 Hz, 1H), 7.66 (dd, J=8.9, 2.5 Hz, 1H), 7.99 (s,2H), 8.26 (s, 1H), 8.72 (s, 1H).

2-{4-Bromo-2-[1-(2,4-dibromophenyl)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid. Prepared from 6-bromo-3-formylchromone, 2,4-dibromophenylhydrazineand ethyl 2-bromopropionate according to GP1, GP2 and GP3: LC/MS(an10p8): Rt 2.87 min, m/z 572.7 [M+H]⁺; ¹H NMR (DMSO): δ 1.32 (d, J=6.8Hz, 3H), 4.93 (q, J=6.8 Hz,1H), 6.91 (d, J=8.9 Hz, 1H), 7.54 (dd, J=8.3,2.3 Hz, 2H), 7.66 (dd, J=8.9, 2.5 Hz, 1H), 7.78 (dd, J=8.6, 2.2 Hz, 1H),8.15 (d, J=2.1 Hz, 1H), 8.21 (s, 1H), 8.72 (s, 1H).

{4-Bromo-2-[1-(2,6-diethyl-phenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid. Prepared from 6-bromo-3-formylchromone, 2,6-diethylphenylhydrazineand ethyl bromoacetate according to GP1, GP2 and GP3: LC/MS (an10n8): Rt2.54 min, m/z 457.0 [M−H]⁺; ¹H NMR (CDCl₃): δ 1.27 (t, J=7.3 Hz, 6H),2.35 (q, J=7.3 Hz, 4H), 4.82 (s, 2H), 6.99 (d, J=8.9 Hz, 1H), 7.29 (d,J=7.5 Hz, 2H), 7.48 (m, 1H), 7.67 (m, 1H), 7.79 (s, 1H), 8.11 (s, 1H),8.27 (s, 1H), 8.87 (br s, 1H).

{4-Bromo-2-[1-(2,6-dimethylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid. Prepared from 6-bromo-3-formylchromone, 2,6-diethylphenylhydrazineand ethyl bromoacetate according to GP1, GP2 and GP3: LC/MS (an10n8): Rt2.27 min, m/z 428.9 [M−H]⁺; ¹H NMR (CDCl₃): δ 2.07 (s, 6H), 4.74 (s,2H), 6.91 (d, J=8.7 Hz, 1H), 7.19 (d, J=7.3 Hz, 2H), 7.25-7.35 (m, 1H),7.55-7.66 (m, 1H), 7.71 (s, 1H), 8.06 (s, 1H), 8.23 (s, 1H), 8.91 (br s,1H).

{4-Bromo-2-[1-(2-ethyl-6-methylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid. Prepared from 6-bromo-3-formylchromone,2-ethyl-6-methylphenylhydrazine and ethyl bromoacetate according to GP1,GP2 and GP3: LC/MS (an10n8): Rt 2.43 min, m/z 443.0 [M−H]⁺; ¹H NMR(CDCl₃): δ 1.12 (t, J=7.8 Hz, 3H), 2.05 (s, 3H), 2.33 (q, J=7.8 Hz, 2H),4.76 (s, 2H), 6.94 (d, J=8.7 Hz, 1H), 7.14-7.25 (m, 2H), 7.31-7.41 (m,1H), 7.56-66 (m, 1H), 7.72 (s, 1H), 8.06 (s, 1H), 8.22 (s, 1H), 8.93 (brs, 1H).

{4-Bromo-2-[1-(2-isopropylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid. Prepared from 6-bromo-3-formylchromone,2-ethyl-6-methylphenylhydrazine and ethyl bromoacetate according to GP1,GP2 and GP3: LC/MS (an10p8): Rt 2.76 min, m/z 444.9 [M+H]⁺; ¹H NMR(CDCl3-d): δ 1.22 (d, J=6.5 Hz, 6H), 2.89 (septet, J=6.1 Hz, 1H), 4.76(s, 2H), 6.92 (d, J=8.7 Hz, 1H), 7.30 (s, 2H), 7.49 (s, 2H), 7.62(d,1H), 7.72 (s, 1H), 8.15 (s, 1H), 8.20 (s, 1H), 8.92 (br s, 1H).

[4-Ethoxy-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetic acid.Prepared from 6-ethoxy-3-formylchromone, phenylhydrazine and ethylbromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt 1.97 min,m/z 367.1 [M+H]⁺; ¹H NMR (CDCl₃): δ 1.43 (t, J=6.8 Hz, 3H), 4.03 (q,J=6.9 Hz, 2H), 4.78 (s, 2H), 7.01-7.13 (m, 2H), 7.15 (s, 1H), 7.36-7.43(m, 1H), 7.46-7.57 (m, 2H), 7.71-7.75 (m, 2H), 8.16 (s, 1H), 8.50 (s,1H).

[4-Butyl-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetic acid. Asolution ofethyl[4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetate (472mg, 1.1 mmol), 1-butylboronic acid (102 mg, 1.0 mmol) and Pd (dppf)Cl₂(72 mg, 0.05 mmol) in THF (10 mL) and water (1 mL) under argon wasrefluxed for 24 h. The reaction mixture was extracted with CH₂Cl₂, theorganic phase was filtered through celite and concentrated, and theresidue was purified by flash chromatography (SiO2, EtOAc:heptane, 1:10to 1:1). The purest fraction was concentrated (˜10 mg), and the residuewas hydrolysed according to GP3: LC/MS (an10p8): Rt 2.59 min, m/z 379.1[M+H]⁺; ¹H NMR (CDCl₃): δ 0.88 (t, J=7.5 Hz, 3H), 1.29 (m, 2H), 1.49 (m,2H), 2.48 (m, 2H), 4.51 (s, 2H), 6.84 (m, 1H), 7.14 (m, 1H), 7.30 (m,2H), 7.42 (m, 2H), 7.65 (m, 2H), 7.97 (s, 1H), 8.46 (s, 1H).

{4-Bromo-2-[1-(2-chloro-6-methylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid. Prepared from 6-bromo-3-formylchromone,2-chloro-6-methylphenylhydrazine and ethyl bromoacetate according toGP1, GP2 and GP3: LC/MS (an10p8): Rt 2.49 min, m/z 450.9 [M+H]⁺; ¹H NMR(CDCl₃): δ 2.16 (s, 3H), 4.80 (s, 2H), 6.98 (d, J=9.1 Hz, 1H), 7.30 (m,1H), 7.34-7.40 (m, 2H), 7.66 (d, 1H), 7.77 (m, 1H), 8.13 (s, 1H); 8.24(s, 1H).

2-{4-Bromo-2-[1-(2,6-dimethylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid. Prepared from 6-bromo-3-formylchromone,2,6-dimethylphenylhydrazine and ethyl 2-bromopropionate according toGP1, GP2 and GP3: LC/MS (an10n8): Rt 2.55 min, m/z 440.9 [M−H]⁺; ¹H NMR(CDCl₃): δ 1.68(d, J=6.8 Hz, 3H), 2.11 (s, 6H), 4.94 (q, J=7.0 Hz 1H),6.97 (d, J=8.9 Hz, 1H), 7.19 (d, J=7.5 Hz 2H), 7.28-7.32 (m, 1H), 7.63(d, J=8.1 Hz, 1H), 7.75 (m, 1H), 8.05 (s, 1H), 8.22 (s, 1H).

2-{4-Bromo-2-[1-(2,6-diethylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid. Prepared from 6-bromo-3-formylchromone, 2,6-diethylphenylhydrazineand ethyl 2-bromopropionate according to GP1, GP2 and GP3: LC/MS(an10n8): Rt 2.85 min, m/z 469.0 [M−H]⁺; ¹H NMR (CDCl₃): δ 1.08-1.21 (m,6H), 1.69-1.76 (m, 3H), 2.18-2.48 (m, 4H), 2.67 (s,1H), 4.97 (q, J=6.8Hz 1H), 6.84 (d, J=9.0 Hz, 1H), 7.00 (d, J=9.0 Hz, 1H), 7.24 (d, J=7.7Hz, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.65 (d, J=9.0 Hz, 1H), 7.77 (s, 1H),7.86 (s, 1H), 8.06 (s, 1H), 8.22 (s, 1H).

2-{4-Bromo-2-[1-(2-isopropylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}propionicacid. Prepared from 6-bromo-3-formylchromone, 2,6-diethylphenylhydrazineand ethyl 2-bromopropionate according to GP1, GP2 and GP3: LC/MS(an10p8): Rt 2.54 min, m/z 459.0 [M+H]⁺; ¹H NMR (CDCl₃): δ 1.19-1.27 (m,7H), 1.67 (d, J=7.0 Hz, 2H), 4.92 (q, J=6.8 Hz, 1H), 6.96 (d, J=8.9 Hz,1H), 7.27-7.53 (m, 4H), 7.58-7.67 (m, 1H), 7.73 (s, 1H), 8.17 (s, 1H),8.20 (s,1H).

{4-Bromo-2-[1-(3,5-dichloropyridin-4-yl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid. Prepared from 6-bromo-3-formylchromone,2,6-dichloropyridine-4hydrazine and ethyl bromoacetate according to GP1,GP2 and GP3: LC/MS (an10n8): Rt 2.08 min, m/z 469.8 [M−H]⁻; ¹H NMR(DMSO-d₆): δ 4.75 (s, 2H), 7.05 (d, J=9.1 Hz, 1H), 7.56 (s, 1H), 7.64(d, J=9.1 Hz, 1H), 8.32 (s, 1H), 8.77 (s, 1H), 8.93 (s, 2H).

{4-Bromo-2-[1-(4-trifluoromethylphenyl)-1H-pyrazole-4-carbonyl]phenoxy}aceticacid. Prepared from 6-bromo-3-formylchromone,4-trifluoromethylphenylhydrazine and ethyl bromoacetate according toGP1, GP2 and GP3: LC/MS (an10n8): Rt 2.88 min, m/z 468.9 [M−H]⁻; ¹H NMR(CDCl₃): δ 4.78 (s, 2H), 6.92 (d, J=8.9 Hz, 1H), 7.65 (d, J=8.9 Hz, 1H),7.71 (s, 1H), 7.79 (d, J=8.9 Hz, 2H), 7.91 (d, J=8.9 Hz, 2H), 8.23 (s,1H), 8.65 (s, 1H).

[4-Bromo-2-(1-naphthalen-1-yl-1H-pyrazole-4-carbonyl)phenoxy]aceticacid. Prepared from 6-bromo-3-formylchromone, 1-naphtylhydrazine andethyl bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt2.649 min, m/z 451.0 [M+H]⁺; ¹H NMR (CDCl₃): δ 4.78 (s, 2H), 6.93 (d,J=8.85 Hz, 1H), 7.52-7.68 (m, 6H), 7.73-7.82 (m, 2H), 7.93-8.05 (m, 2H),8.33 (s, 1H), 8.38 (s, 1H).

General Synthetic Route IV

General Procedure 5 (GP5):

A mixture of ethyl 2-(2-bromoacetyl)phenoxyacetate (0.1 mmol) and amide(X═O) or thioamide (X═S) (2.5 mmol) was heated neat in the microwave for3 hours at 140° C. After cooling, the solid residue was partitionedbetween EtOAc and saturated aq. NaHCO₃. The phases were separated andthe organic phase was dried (MgSO₄) and concentrated in vacuo. The crudesolid was purified by flash chromatography to give the correspondingoxazole or thiazole derivative.

INTERMEDIATE-9

(2-Acetyl-4-bromophenoxy)acetic acid ethyl ester Prepared from5′-bromo-2′-hydroxyacetophenone (2 g, 9.3 mmol) and ethyl bromoacetate(1.03 mL, 9.3 mmol) according to GP2 to give the title compound as awhite solid (2.64 g, 8.7 mmol, 94%): LC/MS (an10p8) Rt 3.3 min, m/z 301[M+H]⁺; ¹H NMR (CDCl₃): δ 1.32 (t, 3H), 2.71 (s, 3H), 4.30 (q, 2H), 4.72(s, 2H), 6.76 (d, 1H), 7.55 (dd, 1H), 7.88 (s, 1H).

INTERMEDIATE-10

[4-Bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester. To a cooled(0° C.) solution of (2-acetyl-4-bromophenoxy)acetic acid ethyl ester(2.5 g, 8.3 mmol) in CHCl₃ (25 mL) was slowly added bromine (425 uL, 8.3mmol). After completion the reaction mixture was allowed to stir at roomtemperature for 1 hour. The mixture was partitioned between CH₂Cl₂ andbrine. The organic phase was washed with brine, dried (MgSO₄) andconcentrated in vacuo to give the title compound as a white solid (2.97g, 7.8 mmol, 94%): ¹H NMR (CDCl₃): δ 1.35 (t, 3H), 4.32 (q, 2H), 4.75(s, 2H), 4.76 (s, 2H), 6.77 (d, 1H), 7.60 (dd, 1H), 7.97 (s, 1H)

[4-Bromo-2-(2-phenyloxazol-4-yl)phenoxy]acetic acid. Title compound wasprepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl esterand benzamide according to GP5 and GP3: LC/MS (an10p8) Rt 2.6 min, m/z374/376 [M+H]⁺.

{4-Bromo-2-[2-(4-methoxyphenyl)oxazol-4-yl]phenoxy}acetic acid. Titlecompound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acidethyl ester and 4-methoxybenzamide according to GP5 and GP3: LC/MS(an10p8) Rt 2.61 min, m/z 404 [M+H]⁺.

{4-Bromo-2-[2-(4-chlorophenyl)oxazol-4-yl]phenoxy}acetic acid. Titlecompound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acidethyl ester and 4-chlorobenzamide according to GP5 and GP3: LC/MS(an10p8) Rt 2.90 min, m/z 407.7 [M+H]⁺; ¹H NMR (CDCl₃): δ 4.89 (s, 2H),7.09 (d, 1H), 7.48 (d, 1H), 7.64 (d, 2H), 8.08 (d, 2H), 8.20 (s, 1H),8.89 (s, 1H), 13.2 (br s, 1H).

{4-Bromo-2-[2-(3-methoxyphenyl)oxazol-4-yl]phenoxy}acetic acid. Titlecompound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acidethyl ester and 3-methoxybenzamide according to GP5 and GP3: LC/MS(an10p8) Rt 2.68 min, m/z 404 [M+H]⁺; ¹H NMR (CDCl₃): δ 3.87 (s, 1H),4.89 (s, 2H), 7.09 (m, 2H), 7.4-7.7 (m, 4H), 8.22 (s, 1H), 8.89 (s, 1H),13.3 (br s, 1H).

{4-Bromo-2-[2-(4-ethoxyphenyl)oxazol-4-yl]phenoxy}acetic acid. Titlecompound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acidethyl ester and 4-ethylbenzamide according to GP5 and GP3: LC/MS(an10p8) Rt 2.80 min, m/z 418/420 [M+H]⁺; ¹H NMR (CDCl₃): δ 1.36 (t,3H), 4.10 (q, 2H), 4.88 (s, 2H), 7.07 (m, 3H), 7.47 (d, 1H), 8.00 (d,2H), 8.20 (s, 1H), 8.82 (s, 1H), 13.4 (br s, 1H).

[2-(2-Benzyloxazol-4-yl)-4-bromophenoxy]acetic acid. Title compound wasprepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl esterand 2-phenylacetamide according to GP5 and GP3: LC/MS (an10p8) Rt 2.47min, m/z 388 [M+H]⁺; ¹H NMR (CDCl₃): δ 4.22 (s, 2H), 4.84 (s, 2H), 7.04(d, 1H), 7.25 (m, 5H), 7.43 (d, 1H), 8.06 (s, 1H), 8.69 (s, 1H), 13 (brs, 1H).

{4-Bromo-2-[2-(3-methoxybenzyl)oxazol-4-yl]phenoxy}acetic acid. Titlecompound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acidethyl ester and 2-(3-methoxyphenyl)acetamide according to GP5 and GP3:LC/MS (an10p8) Rt 2.45 min, m/z 418 [M +H]⁺.

{4-Bromo-2-[2-(2-chloro-4-fluorobenzyl)oxazol-4-yl]phenoxy}acetic acid.Title compound was prepared from[4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and2-(2-chloro-4-fluorophenyl)acetamide according to GP5 and GP3: LC/MS(an10p8) Rt 2.75 min, m/z 440 [M+H]⁺.

{4-Bromo-2-[2-(2,6-dichlorobenzyl)oxazol-4-yl]phenoxy}acetic acid. Titlecompound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acidethyl ester and 2-(2,6-dichlorophenyl)acetamide according to GP5 andGP3: LC/MS (an10p8) Rt 2.75 min, m/z 456/458/460 [M+H]⁺.

{4-Bromo-2-[2-(4-methoxybenzyl)oxazol-4-yl]phenoxy}acetic acid. Titlecompound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acidethyl ester and 2-(4-methoxyphenyl)acetamide according to GP5 and GP3:LC/MS (an10p8) Rt 2.40 min, m/z 418 [M+H]⁺; ¹H NMR (CDCl₃): δ 3.72 (s,3H), 4.14 (s, 1H), 4.85 (s, 1H), 6.92 (m, 2H), 7.02 (d, 1H), 7.2 (d,1H), 7.23 (d, 1H), 7.44 (d, 1H), 8.05 (s, 1H), 8.67 (s, 1H), 13.2 (br s,1H).

[4-Bromo-2-(2-phenylthiazol-4-yl)phenoxy]acetic acid. Title compound wasprepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl esterand thiobenzamide according to GP5 and GP3: LC/MS (an10p8) Rt 2.69 min,m/z 390 [M+H]⁺.

{4-Bromo-2-[2-(4-chlorobenzyl)thiazol-4-yl]phenoxy}acetic acid Titlecompound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acidethyl ester and 2-(4-chlorophenyl)thioacetamide according to GP5 andGP3: LC/MS (an10p8) Rt 2.69 min, m/z 390 [M+H]⁺; ¹H NMR (CDCl₃): δ 4.42(s, 2H), 4.86 (s, 2H), 7.06 (d, 1H), 7.45 (m, 5H), 8.33 (s, 1H), 8.41(s, 1H), 13.2 (br s, 1H).

General Synthetic Route V

General Procedure 6 (GP6)

Synthesis of Carbonylthiazoles

A mixture of the thioamide (1.0 mmol) and N,N-dimethylformamidedimethylacetal (1.2 mmol) was stirred for 1 hour at room temperatureunder argon. The volatile materials were removed under reduced pressurewithout heating to give the corresponding N′-thioaroylformamidine whichwas used without further purification in the next step.

To a solution of the ethyl 2-(2-bromoacetyl)phenoxyacetate (1 mmol) andthe N′-thioaroylformamidine (1 mmol) in benzene (2.6 mL) was added anexcess of triethylamine (5 mmol). After stirring overnight at roomtemperature, solvent was removed in vacuo. The residue was partitionedbetween EtOAc and satureated aq. NaHCO₃. The organic phase was dried(MgSO₄) and concentrated in vacuo. The crude material was purified byflash chromatography to give the thioamide.

[4-Bromo-2-(2-phenylthiazole-5-carbonyl)phenoxy]acetic acid. Titlecompound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acidethyl ester and thiobenzamide according to GP6 and GP3: LC/MS (an10p8)Rt 2.44 min, m/z 418 [M+H]⁺.

General Synthetic Route VI

General Procedure 7 (GP7)

Synthesis of Oxazole

A mixture of benzamide (1.0 mmol) and 2-bromoacetophenone (0.5 mmol) washeated neat in an Emrys Optimizer microwave oven for 3 hours at 140° C.After cooling EtOAc and CH₂Cl₂ were added and the formed precipitate wasfiltered off. The filtrate was concentrated in vacuo and purified byflash chromatography to give the corresponding oxazole.

INTERMEDIATE-11

(4-Bromo-2-carbamoylphenoxy)acetic acid ethyl ester. Prepared frombromosalicylamide and ethyl bromoacetate according GP2: ¹H NMR (CDCl₃):δ 1.35 (t, 3H), 4.34 (q, 2H), 4.73 (s, 2H), 5.87 (br s, 1H), 6.76 (d,1H), 7.56 (d, 1H), 8.33 (br s, 1H), 8.39 (s, 1H).

[4-Bromo-2-(4-phenyl-oxazol-2-yl)-phenoxy]acetic acid. Title compoundwas prepared from (4-bromo-2-carbamoylphenoxy)acetic acid ethyl esterand 2-bromoacetophenone according to GP7: LC/MS (an10p8) Rt 2.32 min,m/z 374/376 [M+H]⁺.

General Synthetic Route VII

General Procedure 8 (GP8):

Synthesis of Hydroximic Acid Chloride

To a solution of the aldoxime (1.0 mmol) in CH₂Cl₂ (1.7 mL) was addedN-chlorosuccinimide (1.0 mmol) in one portion. The reaction mixture wasstirred for 3 hours at room temperature under an argon atmosphere. Waterwas added. The phases were separated. The organic phase was dried(MgSO₄) and concentrated in vacuo to give the corresponding hydroximicacid chloride derivative which was used without further purification.

General Procedure 9 (GP9):

Synthesis of Isoxazole

To a solution of the hydroximic acid chloride (1.0 mmol) and(4-bromo-2-propynoyl-phenoxy)acetic acid ethyl ester (1.0 mmol) in dryCH₂Cl₂ (3.7 mL) was slowly added a solution of Et₃N (1.0 mmol) in dryCH₂Cl₂ (0.6 mL) over a period of 4 hours (use of syringe-pump). Aftercompletion of the addition, the reaction mixture was washed with water,brine, dried (MgSO₄) and concentrated in vacuo. The crude oil waspurified by flash chromatography to give the corresponding isoxazolderivative.

SYNTHESIS OF INTERMEDIATE-12

(4-Bromo-2-formylphenoxy)acetic acid ethyl ester. Prepared from5-bromo-2-hydroxybenzaldehyde according GP2: LC/MS (an10p8) Rt 3.45min,m/z 287 [M+H]⁺; ¹H NMR (CDCl₃): δ 1.29 (t, 3H), 4.25 (q, 2H), 4.74 (s,2H), 6.79 (d, 1H), 7.60 (d, 1H), 7.94 (s, 1H), 10.46 (s, 1H)

[4-Bromo-2-(1-hydroxy-3-trimethylsilanylprop-2-ynyl)phenoxy]acetic acidethyl ester. To a cooled (−78° C.) solution of (trimethylsilyl)acetylene(3.93 g, 40.0 mmol) in dry THF (40 mL) was slowly added a 2.5 M solutionof butyllithium in hexanes (14.54 mL, 36.36 mmol). After stirring for 30minutes at −78° C., the mixture was transferred to a cooled (−78° C.)solution of (4-bromo-2-formylphenoxy)acetic acid ethyl ester (10.44 g,36.36 mmol) in dry THF (120 mL). Upon completion, the reaction mixturewas stirred at −78° C. for 45 minutes. Saturated aq. NH₄Cl (40 mL) wasslowly added to the reaction mixture followed by Et₂O (40 mL). Thequenched reaction mixture was allowed to warm up to room temperature.The phases were separated and the aqueous phase was extracted with Et₂O(2×). The combined organic phases were washed with brine, dried (MgSO₄)and concentrated in vacuo. The crude oil was purified by columnchromatography (SiO₂), then was stirred for 90 min withpolystyrene-supported trisamine (PS-Trisamine, 4.17 mmol/g, 8 g) inCH₂Cl₂ (160 mL). The resin was filtered off and the filtrate wasconcentrated in vacuo to give the title compound as pale yellow oil (7.6g, 19.7 mmol, 54%). LC/MS (an10p8) Rt 4.30 min, m/z 408 [M+Na]⁺; ¹H NMR(CDCl₃): δ 0.24 (s, 9H), 1.31 (t, 3H), 4.27 (q, 2H), 4.71 (s, 2H), 5.79(s, 1H), 6.74 (d, 1H), 7.39 (dd, 1H), 7.79 (d, 1H).

[4-Bromo-2-(3-trimethylsilanylpropynoyl)phenoxy]acetic acid ethyl ester.To a solution of[4-bromo-2-(1-hydroxy-3-trimethylsilanylprop-2-ynyl)phenoxy]acetic acidethyl ester (0.95 g, 2.46 mmol) in CH₂Cl₂ (10 mL) was added activatedMnO₂ in 2 portions (1.5 g+1 g), and the reaction was stirred for 90 min.The solid was filtered off through a celite pad and the filtrate wasconcentrated in vacuo to give the title compound as yellow oil (0.83 g,2.16 mmol, 87%). LC/MS (an10p8) Rt 4.70 min, m/z 383 [M+H]⁺; ¹H NMR(CDCl₃): δ 0.30 (s, 9H), 1.30 (t, 3H), 4.27 (q, 2H), 4.72 (s, 2H), 6.81(d, 1H), 7.58 (dd, 1H), 8.10 (s, 1H).

(4-Bromo-2-propynoylphenoxy)acetic acid ethyl ester. To a solution of[4-bromo-2-(3-trimethylsilanylpropynoyl)phenoxy]acetic acid ethyl ester(0.83 g, 2.16 mmol) in methanol (20 mL) was added a 0.1M aqueoussolution of Na₂B₄O₇ (10 mL). After stirring for 2-3 minutes at roomtemperature, Et₂O and 1N aq. HCl were added. The phases were separated,and the organic phase was washed with brine, dried (MgSO₄) andconcentrated in vacuo to give the title compound as yellow oil whichcrystallized upon standing (0.65 g, 2.09 mmol, 96%). LC/MS (an10p8) Rt3.58 min, m/z 311 [M+H]⁺; ¹H NMR (CDCl₃): δ1.31 (t, 3H), 3.45 (s, 1H),4.27 (q, 2H), 4.74 (s, 2H), 6.83 (d, 1H), 7.61 (dd, 1H), 8.14 (d, 1H).

[4-Bromo-2-(3-phenylisoxazole-5-carbonyl)phenoxy]acetic acid Titlecompound was prepared from benzalddoxime and(4-bromo-2-propynoylphenoxy)acetic acid ethyl ester according to GP8 andGP9: LC/MS (an10n8) Rt 3.07 min, m/z 400 [M−H]⁻; ¹H NMR (DMSO): δ 4.77(s, 2H), 7.13 (d, 1H), 7.53 (m, 3H), 7.73-7.92 (m, 5H).

{4-Bromo-2-[3-(2,6-dichloro-phenyl)isoxazole-5-carbonyl]phenoxy}aceticacid. Title compound was prepared from 2,6-dichlorobenzalddoxime and(4-bromo-2-propynoylphenoxy)acetic acid ethyl ester according to GP8 andGP9: LC/MS (an10n8) Rt 2.74 min, m/z 471.9 [M+H]⁺.

General Synthetic Route VIII

General Procedure 10 (GP10)

Synthesis of Amidoximes

Sodium (1.25 mmol) was added to dry methanol (1 ml) to give solution A.Hydroxylamine hydrochloride (1.2 mmol) was dissolved in dry methanol (1mL) to give solution B. Solution A and B were mixed, cooled in anice-bath and filtered. To the filtrate was then added the nitrile (1mmol) and the reaction mixture was stirred over night at roomtemperature. The solvent was removed in vacuo to give the correspondingamidoxime. The compound was purified over silica gel chromatography(EtOAc/Heptane: 1/2) or used without further purification.

General Procedure 11 (GP11)

Synthesis of Oxadiazoles

To a solution of sodium (3.3 mmol) in dry ethanol (10 mL) weresuccessively added the amidoxime (1.15 mmol), molecular sieves (1 g) andmethyl benzoate (1 mmol). After stirring for 12 h under reflux, thereaction mixture was cooled and filtered through a celite pad. Thecelite pad was washed with methanol and CH₂Cl₂. The solvent was removedin vacuo and the residue was stirred with water. The precipitate wasfiltered off and dried to give the corresponding oxadiazole. Thecompound was purified over silica gel chromatography (EtOAc:Heptane,1:2) or used without further purification in.

[4-Bromo-2-(3-phenyl-[1,2,4]oxadiazol-5-yl)phenoxy]acetic acid. Titlecompound was prepared from 5-bromo-2-hydroxybenzoic acid methyl esterand benzonitrile according to GP10, GP11, GP2 and GP3: LC/MS (an10n8):Rt 2.41 min, m/z 373.4 [M−H]⁻; ¹H NMR (DMSO-d₆): δ 4.97 (s, 2H), 7.2 (d,1H), 7.62 (s, 3H), 7.82 (d, 2H), 8.10 (d, 1H), 8.2 (s, 1H).

{4-Bromo-2-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and 4-fluorobenzonitrile according to GP10, GP11, GP2 andGP3: LC/MS (an10n8) Rt 2.49, m/z 391.4 [M−H]⁻.

{4-Bromo-2-[3-(4-methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and 4-methoxybenzonitrile according to GP10, GP11, GP2 andGP3: LC/MS (an10n8) Rt 2.44 min, m/z 403.4 [M−H]⁻.

{4-Bromo-2-[3-(4-chlorophenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and 4-chlorobenzonitrile according to GP10, GP11, GP2 andGP3: LC/MS (an10n8) Rt 2.68 min, m/z 407.4 [M−H]⁻.

{4-Bromo-2-[3-(4-trifluoromethoxyphenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and 4-trifluoromethoxybenzonitrile according to GP10, GP11,GP2 and GP3: LC/MS (an10n8) Rt 2.09 min, m/z 457.5 [M−H]⁻; ¹H NMR(DMSO-d₆): δ 4.96 (s, 2H), 7.21 (d, 1H), 7.59 (d, 2H), 7.82 (d, 1H),8.22 (d, 3H).

{4-Bromo-2-[3-(3-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and 3-methoxybenzonitrile according to GP10, GP11, GP2 andGP3: LC/MS (an10n8) Rt 2.47 min, m/z 403.4 [M−H]⁻; ¹H NMR (DMSO-d₆): δ3.86 (s, 3H), 4.96 (s, 2H), 7.20 (d, 2H), 7.5 (t, 1H), 7.6 (s, 1H), 7.67(d,1H), 7.8 (d, 1H), 8.2 (s, 1H).

{4-Bromo-2-[3-(3-chlorophenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and 3-chlorobenzonitrile according to GP10, GP11, GP2 andGP3: LC/MS (an10n8) Rt 2.69 min, m/z 407.4 [M−H]⁻; ¹H NMR (DMSO): δ 4.97(s, 2H), 7.2 (d, 1H), 7.6 (m, 2H), 7.7 (d, 1H), 7.8 (d 2H), 8.2, (s,1H).

{4-Bromo-2-[3-(4-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}-aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and 4-trifluoromethylbenzonitrile according to GP10, GP11,GP2 and GP3: LC/MS (an10n8) Rt 2.83 min, m/z 441.4 [M−H]⁻; ¹H NMR(DMSO-d₆): δ 4.97 (s, 2H), 7.2 (d, 1H), 7.8 (dd, 1H), 7.9 (d, 2H), 8.2(d, 1H), 8.3 (d, 2H).

{4-Bromo-2-[3-(2-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and 2-methoxybenzonitrile according to GP10, GP11, GP2 andGP3: LC/MS (an10n8) Rt 2.31 min, m/z 403.4 [M−H]⁻; ¹H NMR (DMSO-d₆): δ2.5 (s, 3H), 4.94 (s, 2H), 7.2 (m, 3H), 7.5 (t, 1H), 7.7 (d, 1H), 7.9(d, 1H), 8.1 (s, 1H).

{4-Bromo-2-[3-(2-chlorophenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and 2-chlorobenzonitrile according to GP10, GP11, GP2 andGP3: LC/MS (an10n8) Rt 2.50 min, m/z 407.4 [M−H]⁻; ¹H NMR (DMSO-d₆): δ4.94 (s, 2H), 7.2 (d, 1H), 7.5-7.7 (m, 3H), 7.8 (dd, 1H), 8.0 (d, 1H),8.1 (s,1H).

{2-[3-(3,5-Bis-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-4-bromo-phenoxy}-aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and 3,5-bistrifluoromethoxybenzonitrile according to GP10,GP11, GP2 and GP3: LC/MS (an10n8) Rt 3,332 min, m/z 509.5 [M−H]⁻; ¹H NMR(DMSO-d₆): δ4.96 (s, 2H), 7.2 (d, 1H), 7.8 (d, 1H), 8.2 (s, 1H), 8.4(s,1H), 8.5 (s, 1H), 8.6 (s, 1H).

{4-Bromo-2-[3-(2,6-dichlorophenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and 2,6-Dicholoro-benzonitrile according to GP10, GP11, GP2and GP3: LC/MS (an10n8) Rt 2.59 min, m/z 441.4 [M−H]⁻.

{4-Bromo-2-[3-(4-phenoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-phenoxy}-aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and 4-phenoxybenzonitrile according to GP10, GP11, GP2 andGP3: LC/MS (an10n8) Rt 3.29 min, m/z 465.5 [M−H]⁻; ¹H NMR (DMSO-d₆): δ4.95 (s,2H), 7.2 (m, 6H), 7.4 (t, 2H), 7.8 (d, 1H), 8.0 (d, 2H), 8.1 (s,1H).

{4-Bromo-2-[3-(3-trifluoromethylphenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}-aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and 3-trifluoromethylbenzonitrile according to GP10, GP11,GP2 and GP3: LC/MS (an10n8) Rt 2.96 min, m/z 441.4 [M−H]⁻; ¹H NMR(DMSO-d₆): δ 4.97 (s,2H), 7.2 (d, 1H), 7.8 (m, 2H), 8.0 (d, 1H), 8.2 (s,1H), 8.3 (s, 1H), 8.4 (d, 1H).

{4-Bromo-2-[3-(4-trifluoromethoxy-benzyl)-[1,2,4]oxadiazol-5-yl]-phenoxy}-aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and (4-trifluoromethoxyphenyl)acetonitrile according toGP10, GP11, GP2 and GP3: LC/MS (an10n8) Rt 2.76 min, m/z 4715 [M−H]⁻; ¹HNMR (DMSO-d₆): δ 4.2 (s, 2H), 4.9 (s, 2H), 7.1 (d, 1H), 7.3 (d, 2H), 7.5(d, 2H), 7.7 (d, 1H), 8.0 (s, 1H).

{4-Bromo-2-[3-(4-chloro-benzyl)-[1,2,4]oxadiazol-5-yl]-phenoxy}-aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and (4-chlorophenyl)acetonitrile according to GP10, GP11,GP2 and GP3: LC/MS (an10n8) Rt 2.54 min, m/z 421.4 [M−H]⁻; ¹H NMR(DMSO-d₆): δ 4.2 (s, 2H), 4.9 (s, 2H), 7.1 (d, 1H), 7.4 (s, 4H), 7.8 (d,1H), 8.0 (s, 1H).

[2-(3-Benzyl-[1,2,4]oxadiazol-5-yl)-4-bromo-phenoxy]-acetic acid. Titlecompound was prepared from 5-bromo-2-hydroxybenzoic acid methyl esterand phenylacetonitrile according to GP10, GP11, GP2 and GP3: LC/MS(an10n8) Rt 2.26 min, m/z 387.4 [M−H]⁻; ¹H NMR (DMSO-d₆): δ 4.2 (s, 2H),4.9 (s, 2H), 7.1 (d, 1H), 7.3 (m, 5H), 7.7 (d, 1H), 8.0 (s, 1H).

{4-Bromo-2-[3-(4-fluoro-benzyl)-[1,2,4]oxadiazol-5-yl]-phenoxy}-aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and (4-fluorophenyl)acetonitrile according to GP10, GP11,GP2 and GP3: LC/MS (an10n8) Rt 2.38 min, m/z 405.4 [M−H]⁻.

{4-Bromo-2-[3-(3,5-difluoro-benzyl)-[1,2,4]oxadiazol-5-yl]-phenoxy}-aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and (3,5-difluorophenyl)acetonitrile according to GP10,GP11, GP2 and GP3: LC/MS (an10n8) Rt 2.44 min, m/z 423.4 [M−H]⁻.

{4-Bromo-2-[3-(4-methoxy-benzyl)-[1,2,4]oxadiazol-5-yl]-phenoxy}-aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and (4-methoxyphenyl)acetonitrile according to GP10, GP11,GP2 and GP3: LC/MS (an10n8) Rt 2.25 min, m/z 417.4 [M−H]⁻; ¹H NMR(DMSO-d₆): δ 4.1 (s, 2H), 4.9 (s, 2H), 6.9 (d, 2H), 7.1 (d, 1H), 7.2 (d,2H), 7.7 (d, 1H), 8.0 (s, 1H).

{4-Bromo-2-[3-(2-methoxy-benzyl)-[1,2,4]oxadiazol-5-yl]-phenoxy}-aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and (2-Methoxy-phenyl)-acetonitrile according to GP10,GP11, GP2 and GP3: LC/MS (an10n8) Rt 2.25 min, m/z 417.4 [M−H]⁻; ¹H NMR(DMSO-d₆): δ 3.7 (s, 3H), 4.1 (s, 2H), 4.9 (s, 2H), 6.9 (t, 1H), 7.0 (d,1H), 7.1 (d, 1H), 7.2 (m, 2H), 7.7 (d, 1H), 8.0 (s, 1H).

{4-Bromo-2-[3-(2-chloro-benzyl)-[1,2,4]oxadiazol-5-yl]-phenoxy}-aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and (2-chlorophenyl)acetonitrile according to GP10, GP11,GP2 and GP3: LC/MS (an10n8) Rt 2.48 min, m/z 421.4 [M−H]⁻; ¹H NMR(DMSO-d₆): δ 4.2 (s, 2H), 4.9 (s, 2H), 7.1 (d, 1H), 7.3 (m, 2H), 7.4 (m,2H), 7.7 (dd, 1H), 8.0 (d, 1H).

{4-Bromo-2-[3-(2,6-dichloro-benzyl)-[1,2,4]oxadiazol-5-yl]-phenoxy}-aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and (2,6-dichlorophenyl)acetonitrile according to GP10,GP11, GP2 and GP3: LC/MS (an10n8) Rt 2.58 min, m/z 455/457/459 [M−H]⁻;¹H NMR (DMSO-d₆): δ 4.4 (s, 2H), 4.9 (s, 2H), 7.1 (d, 1H), 7.4 (t, 1H),7.5 (d, 2H), 8.7-7.8 (dd, 1H), 8.0 (d, 1H).

{4-Bromo-2-[3-(2,4-dichloro-benzyl)-[1,2,4]oxadiazol-5-yl]-phenoxy}-aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and (2,4-dichlorophenyl)acetonitrile according to GP10,GP11, GP2 and GP3: LC/MS (an10n8) Rt 2,78 min, m/z 455/457/459 [M−H]⁻.

{4-Bromo-2-[3-(3,4-dichlorobenzyl)-[1,2,4]oxadiazol-5-yl]-phenoxy}aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and (3,4-dichlorophenyl)acetonitrile according to GP10,GP11, GP2 and GP3: LC/MS (an10n8) Rt 2.81 min, m/z 455/457/459 [M−H]⁻;¹H NMR (DMSO-d₆): δ 4.3 (s, 2H), 4.8 (s, 2H), 7.1 (d, 1H), 7.3 (dd, 1H),7.6 (d, 1H), 7.6 (d, 1H), 7.7 (dd, 1H), 8.0 (d, 1H).

{4-Bromo-2-[3-(3,4-dimethoxybenzyl)-[1,2,4]oxadiazol-5-yl]phenoxy}-aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and (3,4-bismethoxyphenyl)acetonitrile according to GP10,GP11, GP2 and GP3: LC/MS (an10n8) Rt 2.20 min, m/z 447.4 [M−H]⁻; ¹H NMR(DMSO-d₆): δ 3.72 (s, 3H), 3.74 (s, 3H), 4.1 (s, 2H), 4.9 (s, 2H), 6.8(m, 2H), 6.9 (s, 1H), 7.1 (d, 1H), 7.7 (dd, 1H), 8.0 (d, 1H).

{4-Bromo-2-[3-(3-methoxybenzyl)-[1,2,4]oxadiazol-5-yl]phenoxy}aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and (3-methoxyphenyl)acetonitrile according to GP10, GP11,GP2 and GP3: LC/MS (an10n8) Rt 2.38 min, m/z 417.4 [M−H]⁻; ¹H NMR(DMSO-d₆): δ 4.1 (s, 2H), 4.9 (s, 2H), 6.8 (d, 1H), 6.9 (m, 2H), 7.1 (d,1H), 7.2 (t, 1H), 7:8 (m, 1H), 8.0 (d, 1H).

{4-Bromo-2-[3-(4-methylbenzyl)-[1,2,4]oxadiazol-5-yl]phenoxy}aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and (4-methylphenyl)acetonitrile according to GP10, GP11,GP2 and GP3: LC/MS (an10n8) Rt 2.72 min, m/z 401.4 [M−H]⁻; ¹H NMR(DMSO-d₆): δ 3.3 (s, 3H), 4.1 (s, 2H), 4.9 (s, 2H), 7.1 (m, 3H), 7.2 (d,2H), 7.7 (dd, 1H), 8.0 (d, 1H).

{4-Bromo-2-[3-(2-trifluoromethylbenzyl)-[1,2,4]oxadiazol-5-yl]phenoxy}-aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and (2-trifluoromethylphenyl)acetonitrile according toGP10, GP11, GP2 and GP3: LC/MS (an10n8) Rt 2.77 min, m/z 455.5 [M−H]⁻;¹H NMR (DMSO-d₆): δ 4.3 (s, 2H), 4.9 (s, 2H), 7.1 (d, 1H), 7.5-7.6 (m,2H), 7:6-7.7 (t, 1H), 7.7-7.8 (m, 2H), 8.0 (d, 1H).

{4-Bromo-2-[3-(3,5-dimethoxybenzyl)-[1,2,4]oxadiazol-5-yl]phenoxy}aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and (3,5-bismethoxyphenyl)acetonitrile according to GP10,GP11, GP2 and GP3: LC/MS (an10n8) Rt 2.61 min, m/z 447.4 [M−H]⁻; ¹H NMR(DMSO-d₆): δ 3.7 (s, 6H), 4.1 (s, 2H), 4.9 (s, 2H), 6.4 (d, 1H), 6.5 (d,2H), 7.1 (d, 1H), 7.8 (dd, 1H), 8.0 (d, 1H).

{4-Bromo-2-[3-(2,4-dichlorophenyl)-[1,2,4]oxadiazol-5-yl]phenoxy}aceticacid. Title compound was prepared from 5-bromo-2-hydroxy-benzoic acidmethyl ester and 2,4-dichlorobenzonitrile according to GP10, GP11, GP2and GP3: LC/MS (an10n8) Rt 2.93 m/z 441/443/445 [M−H]⁻; ¹H NMR (DMSO): δ4.7 (s, 1H), 6.95-6.98 (d, 1H), 7.42-7.44 (d, 1H), 7.58-7.60 (d, 1H),7.67 (s, 1H), 7.82-7.85 (d, 1H), 7.94-7.95 (s, 1H).

{4-Bromo-2-[3-(3-chlorobenzyl)-[1,2,4]oxadiazol-5-yl]phenoxy}aceticacid. Title compound was prepared from 5-bromo-2-hydroxy-benzoic acidmethyl ester and 3-chlorophenylacetonitrile according to GP10, GP11, GP2and GP3: LC/MS (an10n8) Rt 2.79 m/z 421.4 [M−H]⁻; ¹H NMR (DMSO): δ 4.21(s, 2H), 4.92 (s, 2H), 7.15-7.18(d, 1H), 7.32-7.39(m, 3H), 7.45 (s, 1H),7.76-7.80 (dd, 1H), 8.03-8.04 (d, 1H).

{2-[3-(4-Acetylaminobenzyl)-[1,2,4]oxadiazol-5-yl]-4-bromophenoxy}aceticacid. Title compound was prepared from 5-bromo-2-hydroxybenzoic acidmethyl ester and 4-acetamidophenylacetonitrile according to GP10, GP11,GP2 and GP3: LC/MS (an10n8) Rt 2.15 m/z 444.4 [M−H]⁻; ¹H NMR (DMSO): δ2.02 (s, 3H), 4.10 (s, 2H), 4.92 (s, 2H), 7.14-7.17(d, 1H), 7.25-7.27(d,2H), 7.52-7.54 (d, 2H), 7.76-7.78 (d, 1H), 8.03 (s, 1H).

{4-Bromo-2-[3-(1-phenylcyclopropyl)-[1,2,4]oxadiazol-5-yl]phenoxy}aceticacid. Title compound was prepared from 5-bromo-2-hydroxy-benzoic acidmethyl ester and 1-phenyl-1-cyclopropanecarbonitrile according to GP10,GP11, GP2 and GP3: LC/MS (an10n8) Rt.2.756 m/z 413.4 [M−H]⁻; ¹H NMR(DMSO-d₆): δ 0.92 (m, 2H), 1.11 (m, 2H), 4.38 (s, 2H), 6.63-6.66 (d,1H), 6.79-6.88 (m, 3H), 6.93-6.95 (m, 2H), 7.25-7.29 (dd, 1H), 7.50-7.51(d, 1H).

[4-Bromo-2-(3-pyridin-[1,2,4]oxadiazol-5-yl)phenoxy]acetic acid. Titlecompound was prepared from 5-bromo-2-hydroxybenzoic acid methyl esterand Pyridine-2-carbonitrile according to GP10, GP11, GP2 and GP3: LC/MS(an10n8) Rt 1.89 min, m/z 374.4 [M−H]⁻; ¹H NMR (DMSO-d₆): δ 4.9 (s, 2H),7.2 (d, 1H), 7.6 (m, 1H), 7.8 (d, 1H), 8.0 (t, 1H), 8.2 (m, 2H), 8.8 (d,1H).

General Synthetic Route IX

{4-Bromo-2-[5-(4′-methoxybiphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]phenoxy}aceticacid. Title compound was prepared from 2-hydroxy-5-bromo-benzonitrileand 4′-methoxy-biphenyl-4-carboxylic acid methyl ester according toGP10, GP11, GP2 and GP3: LC/MS (an10n8) Rt 2.96 min, m/z 479.5 [M−H]⁻.

{4-Bromo-2-[5-(4-chlorophenyl)-[1,2,4]oxadiazol-3-yl]phenoxy}aceticacid. Title compound was prepared from 2-hydroxy-5-bromo-benzonitrileand 4-chlorobenzoic acid methyl ester according to GP10, GP11, GP2 andGP3: LC/MS (an10n8) Rt 2.61 min, m/z 407.4 [M−H]⁻; ¹H NMR (DMSO-d₆): δ4.3 (s, 2H), 6.9 (d, 1H), 7.6 (dd, 1H), 7.7 (d, 2H), 8.0 (d, 1H), 8.2(d, 2H).

{4-Bromo-2-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]phenoxy}aceticacid. Title compound was prepared from 2-hydroxy-5-bromobenzonitrile and3-chlorobenzoic acid methyl ester according to GP10, GP11, GP2 and GP3:LC/MS (an10n8) Rt 2.61 min, m/z 407.4 [M−H]⁻; ¹H NMR (DMSO-d₆): δ 4.4(s, 2H), 6.9 (d, 1H), 7.6 (m, 2H), 7.8 (d, 1H), 8.0 (s, 1H), 8.2 (m,2H).

{4-Bromo-2-[5-(2-chlorophenyl)-[1,2,4]oxadiazol-3-yl]phenoxy}aceticacid. Title compound was prepared from 2-hydroxy-5-bromobenzonitrile and2-chlorobenzoic acid methyl ester according to GP10, GP11, GP2 and GP3:LC/MS (an10n8) Rt 2.45 min, m/z 407.4 [M−H]⁻; ¹H NMR (DMSO-d₆): δ 4.3(s, 2H), 6.9 (d, 1H) 7.6-7.7 (m, 4H), 8.0 (s, 1H), 8.2 (d, 1H).

[4-Bromo-2-(5-phenyl-[1,2,4]oxadiazol-3-yl)phenoxy]acetic acid. Titlecompound was prepared from 2-hydroxy-5-bromobenzonitrile and benzoicacid methyl ester according to GP10, GP11, GP2 and GP3: LC/MS (an10n8)Rt 2.33 min, m/z 373.4 [M−H]⁻; ¹H NMR (DMSO-d₆): δ 4.8 (s, 2H), 7.1 (d,1H), 7.6-7.7 (m, 4H), 8.0 (d, 1H), 8.2 (d, 2H).

General Synthetic Route X

INTERMEDIATE-13

4-Bromo-2-[(ethoxycarbonylmethylamino)methyl]phenoxyacetic acid ethylester. 4-Bromo-2-formylphenoxyacetic acid ethyl ester (1.44 g, 5 mmol)was dissolved in dichloromethane (50 mL) and glycine ethyl esterhydrochloride (1.39 g, 10 mmol) as well as Et₃N (1.4 mL, 10 mmol) wasadded. The mixture was stirred at room temperature for 4 h. Water anddichloromethane was added and the organic phase was passed through aphase separation filter and then evaporated to give{4-bromo-2-[(E)-ethoxycarbonylmethylimino-methyl]phenoxy}acetic acidethyl ester, which was redissolved in dichloromethane (50 mL) andtreated with NaBH(OAc)₃ (2.11 g, 10 mmol) and AcOH (1 mL), and thenstirred at room temperature for 5 h. Saturated Na₂CO₃, water anddichloromethane was added, and the organic phase was passed through aphase separation filter and evaporated to give the title compound (1.56g, 84% overall yield).

General Procedure 12 (GP12)

Reaction with Isocyanates Followed by Ringclosure/Hydrolysis

The aldehyde (0.6 mmol) was dissolved in dichloromethane (6 mL), and theisocyanate (1.2 mmol) and Et₃N (176 μL, 1.26 mmol) was added. Themixture was stirred at room temperature overnight. Then glycine (150 mg,2 mmol) was added (as scavenger for excess isocyanate) and the mixturewas stirred for additional 2 h. Finally water and dichloromethane wasadded and the organic phase was passed through a phase separation filterand then evaporated to give the urea, which was dissolved in acetic acid(3.5 mL) and placed in a sealed glass vial. Then 4 M HCl (3.5 mL) wasadded and the mixture heated by microwaves to 100° C. for 900 s. Aftercooling to room temperature a white precipitate was formed, and thehydantoin was obtained after filtration and washing with water. In caseswhere the product did not precipitate after the hydrolysis,dichloromethane and water was added to the mixture, and the organicphase was passed through a phase separation filter. Evaporation of theorganic phase gave the product, which in some cases was further purifiedon a 1 g SAX Acetate SPE column (equilibrated with 100% MeOH and theneluted with 10% AcOH in MeOH).

4-Bromo-2-[3-(4-chlorobenzyl)-2,4-dioxoimidazolidin-1-ylmethyl]phenoxyaceticacid. Prepared from4-bromo-2-[(ethoxycarbonylmethylamino)methyl]phenoxyacetic acid ethylester (235 mg, 0.63 mmol) and 4-chlorobenzylisocyanate (166 μL, 1.26mmol) according to GP12 (yield: 183.4 mg, 62%): LC/MS (an10p8): Rt 2.3min, m/z 465 [M−H]⁻; ¹H NMR (DMSO-d₆): δ 4.05 (s, 2H), 4.48 (s, 2H),4.55 (s, 2H), 4.73 (s, 2H), 6.92 (d, J=8.3 Hz, 1H), 7.25-7.45 (m, 6H),13.11 (br. s, 1H).

4-Bromo-2-(2,4-dioxo-3-phenethylimidazolidin-1-ylmethyl)phenoxyaceticacid. Prepared from4-bromo-2-[(ethoxycarbonylmethylamino)methyl]phenoxyacetic acid ethylester and phenethylisocyanate according to GP12: LC/MS (an10p8): Rt 2.2min, m/z 445 [M−H]⁻; ¹H NMR (DMSO-d₆): δ 2.84 (t, J=7.2 Hz, 2H), 3.59(t, J=7.2 Hz, 2H), 3.94 (s, 2H), 4.45 (s, 2H), 4.76 (s, 2H), 6.93 (d,J=8.6 Hz, 1H), 7.17-7.46 (m, 7H), 12.45 (br. s, 1H).

General Synthetic Route XI

General Procedure 13 (GP13)

N-Alkylation

The 2-[2,4-dioxothiazolidin-(5Z)-ylidenemethyl]phenoxyacetic acid ethylester (0.85 mmol), Cs₂CO₃ (326 mg, 1.0 mmol), and acetonitrile (10 mL)was mixed in a sealed glass vial. Then the alkylating agent (1.0 mmol)was added and the mixture heated by microwaves to 120° C. for 600 s.Water was added and the mixture was extracted with dichloromethane. Theorganic phase was passed through a phase separation filter and thenevaporated. The product was used directly in the next step or purifiedby column chromatography (SiO₂).

General Procedure 14 (GP14)

Hydrogenation

The 5-benzylidenylthiazolidine-2,4-dione (˜0.8 mmol), ammonium formate(1.0 g, 16 mmol), Pt/C (5 wt %, 500 mg, 0.13 mmol), and acetic acid (12mL) was mixed in a sealed glass vial and heated by microwaves to 135° C.for 1800 s. Then methanol (15 mL) was added and the mixture was filteredthrough a 20 μm PE filter and then through a 1 g SAX Acetate SPE column,which was washed with additional methanol (10 mL). After evaporation ofthe methanol, dichloromethane and water was added, and the organic phasewas passed through a phase separation filter and concentrated to givethe product, which was used directly or purified by columnchromatography on SiO₂.

General Procedure 15 (GP15)

Alkylation of 5-Position of thiazolidine-2,4-diones

3-Alkyl-5-arylmethylthiazolidine-2,4-dione (0.15 mmol), methyl iodide(28 μL, 0.45 mmol), Cs₂CO₃ (147 mg, 0.45 mmol), and acetonitrile (10 mL)was mixed in a sealed glass vial and heated by microwaves to 120° C. for3600 s. Water and dichloromethane was added and the organic phase waspassed through a phase separation filter and then evaporated to give theproduct, which was used directly for the hydrolysis.

General Procedure 16 (GP16)

Acidic Ester Hydrolysis

The ethyl phenoxyacetate (0.02-0.2 mmol) was dissolved in acetic acid (5mL), 4M HCl (5 mL) was added and the mixture was heated by microwaves to100° C. for 900 s. After cooling to room temperature a white precipitatewas formed, which was filtered of, washed with water and dried to givethe product. In cases where the product did not precipitate after thehydrolysis, dichloromethane was added, the organic phase was washed withwater and concentrated, and the residue was purified on a 1 g SAXAcetate SPE column (equilibrated with 100% MeOH and then eluted with 10%AcOH in MeOH) to give the product.

INTERMEDIATE-14

4-Bromo-2-[2,4-dioxothiazolidinylidenemethyl]phenoxyacetic acid ethylester. 4-Bromo-2-formylphenoxyacetic acid ethyl ester (2.47 g, 8.7mmol), 2,4-thiazolidinedione (1.13 g (90%), 8.7 mmol), and ammoniumacetate (671 mg, 8.7 mmol) was mixed with toluene (9 mL) in a sealedvial and heated by microwaves to 120° C. for 600 s. After cooling toroom temperature and scratching the inside of the glass, the productprecipitated out. The precipitate was filtered and washed with tolueneto give the title compound as a yellow solid (2.38 g, 71%).

4-Bromo-2-[3-(4-chlorobenzyl)-2,4-dioxothiazolidin-5-ylmethyl]phenoxyaceticacid. Prepared from 4-chlorobenzylbromide and4-bromo-2-[2,4-dioxothiazolidin-(5Z)-ylidenemethyl]phenoxyacetic acidethyl ester according to GP13, GP14 and GP16 to give 50.4 mg (21%overall yield) of the title compound: LC/MS (an10p8): Rt 2.6 min, m/z482 [M−H]⁻. ¹H NMR (DMSO-d₆): δ 3.05 (dd, J=13.8, 9.7 Hz, 1H), 3.57 (dd,J=13.8, 4.9 Hz, 1H), 5.11 (dd, J=9.7, 4.9 Hz, 1H), 4.67 (s, 2H), 4.75(s, 2H), 6.91 (d, J=8.7, 1H), 7.25-7.28 (m, 2H), 7.37-7.42 (m, 4H),13.15 (br. s, 1H).

4-Bromo-2-[3-(4-methylbenzyl)-2,4-dioxothiazolidin-5-ylmethyl]phenoxyaceticacid. Prepared from 4-methylbenzylbromide and4-bromo-2-[2,4-dioxothiazolidin-(5Z)-ylidenemethyl]phenoxyacetic acidethyl ester according to GP13, GP14 and GP16 (yield: 14 mg, 21%): LC/MS(an10p8): Rt 2.5 min, m/z 462 [M−H]⁻. ¹H NMR (DMSO-d₆): δ 2.98-3.07 (m,1H), 3.53-3.59 (m, 1H), 4.63 (s, 2H), 4.74 (s, 2H), 5.07-5.13 (m, 1H),6.89-6.91 (m, 1H), 7.11-7.16 (m, 4H), 7.38-7.43 (m, 2H), 13.11 (br s,1H).

4-Bromo-2-{3-[2-(4-chlorophenyl)-2-oxoethyl]-2,4-dioxothiazolidin-5-ylmethyl}phenoxyaceticacid. Prepared from 2-bromo-1-(4-chlorophenyl)ethanone and4-bromo-2-[2,4-dioxothiazolidin-(5Z)-ylidenemethyl]phenoxyacetic acidethyl ester according to GP13, GP14 and GP16 (yield: 8.2 mg, 34%): LC/MS(an10p8): Rt 2.8 min, m/z 510 [M−H]⁻. ¹H NMR (DMSO-d6): δ 3.01-3.09 (m,1H), 3.57-3.63 (m, 1H), 4.79 (s, 2H), 5.17 (s, 2H), 5.21-5.24 (m, 1H),6.91-6.95 (m, 1H), 7.44 (m, 2H), 7.66-7.69 (m, 2H), 8.07-8.09 (m, 2H).

4-Bromo-2-[3-(3-chlorobenzyl)-2,4-dioxothiazolidin-5-ylmethyl]phenoxyaceticacid (7d). Prepared from 3-chlorobenzyl bromide and4-bromo-2-[2,4-dioxothiazolidin-(5Z)-ylidenemethyl]phenoxyacetic acidethyl ester according to GP13, GP14 and GP16: LC/MS (an10p8): Rt 2.6min, m/z 484 [M+H]⁺. ¹H NMR (DMSO-d6): δ 3.02-3.10 (m, 1H), 3.54-3.60(m, 1H), 4.69 (s, 2H), 4.75 (s, 2H), 5.09-5.14 (m, 1H), 6.89-6.92 (m,1H), 7.18 (m, 1H), 7.33-7.43 (m, 5H), 13.01 (br s, 1H).

4-Bromo-2-(2,4-dioxo-3-pyridin-4-ylmethylthiazolidin-5-ylmethyl)phenoxyaceticacid. Prepared from 4-bromomethylpyridine and4-bromo-2-[2,4-dioxothiazolidin-(5Z)-ylidenemethyl]phenoxyacetic acidethyl ester according to GP13, GP14 and GP16: LC/MS (an10p8): Rt 2.1min, m/z 451 [M+H]⁺.

4-Bromo-2-[3-(4-chlorobenzyl)-5-methyl-2,4-dioxothiazolidin-5-ylmethyl]phenoxyaceticacid. Prepared from 4-bromomethylpyridine according to GP13, GP14, GP15and GP16 (yield: 29 mg, 15%): LC/MS (an10p8): Rt 3.0 min, m/z 496[M−H]⁻; ¹H NMR (DMSO-d6): 1.71 (s, 3H), 3.24 (d, J=13.8 Hz, 1H), 3.39(d, J=13.8 Hz, 1H), 4.63-4.68 (m, 4H), 6.86 (d, J=8.6 Hz, 1H), 7.13-7.43(m, 6H), 13.08 (br s, 1H).

4-Bromo-2-[3-(2,6-dichlorobenzyl)-5-methyl-2,4-dioxothiazolidin-5-ylmethyl]phenoxyaceticacid. Prepared from 2,6-dichlorobenzylbromide according to GP13, GP14,GP15 and GP16 to give 21.1 mg of the title compound: LC/MS (an10n8): Rt2.9 min, m/z 532 [M−H]⁻; ¹H NMR (DMSO-d₆): δ 1.63 (s, 3H), 3.16 (d,J=13.6 Hz, 1H), 3.40 (d, J=13.6 Hz, 1H), 4.65 (s, 2H), 4.92 (s, 2H),6.86 (d, J=8.9 Hz, 1H), 7.21 (d, J=2.5 Hz, 1H), 7.35-7.48 (m, 4H), 12.38(br s, 1H).

4-Bromo-2-[3-(2-chlorobenzyl)-5-methyl-2,4-dioxothiazolidin-5-ylmethyl]phenoxyaceticacid. Prepared from 2-chlorobenzylbromide according to GP13, GP14, GP15and GP16 to give 22.0 mg of the title compound: LC/MS (an10n8): Rt 2.8min, m/z 498 [M−H]⁻; ¹H NMR (DMSO-d₆): δ 1.76 (s, 3H), 3.28 (d, J=13.7Hz, 1H), 3.43 (d, J=13.7 Hz, 1H), 4.67 (d, J=3.2 Hz, 2H), 4.73 (s, 2H),6.81 (d, J=8.9 Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 7.24-7.36 (m, 3H),7.43-7.50 (m, 2H), 12.18 (br s, 1H).

Biological Assays

Materials and Methods

Generation/origin of the cDNA Constructs. The coding sequence of thehuman CRTH2 receptor (genbank accession no NM_(—)004778) was amplifiedby PCR from a human hippocampus cDNA library and inserted into thepcDNA3.1(+) expression vector (invitrogen) via 5′ HindIII and 3′ EcoRI.To generate a CRTH2-Renilla luciferase (CRTH2-Rluc) fusion protein, theCRTH2 coding sequence without a STOP codon and Rluc were amplified,fused in frame by PCR and subcloned into the pcDNA3.1(+)Zeo expressionvector (invitrogen). Human β-arrestin2 (β-arr2) N-terminally tagged withGFP² (βarr2-GFP²) and Renilla luciferase were purchased from BioSignalPackard Inc, (Montreal, Canada). The sequence identity of the constructwas verified by restriction endonuclease digests and sequencing in bothdirections on an ABI Prism (Applied Biosystems, Foster City, Calif.).

Sequence ID CRTH2 (protein sequence (SEQ ID NO: 1):MSANATLKPLCPILEQMSRLQSHSNTSIRYIDHAAVLLHGLASLLGLVE NGVILFVVGCRMRQTVVTTWVLHLALS D LLASASLPFFTYFLAVGHSWELG TTF CKLHSSIFFLNMFASGFLLSAISLDRCLQVVRPVWAQNHRTVAAAHK VCLVL WALAVLNTVPYFVFRDTISRLDGRIMCYYNVLLLNPGPDRDATCN SRQAALAVSKFLLAFLV PLAIIASSHAAVSLRLQHRGRRRPGREVRLVAA VVAAFALCWG PYHVFSLLEARAHANPGLRPLVWRGLPFVTSLAFFNSVAN PVLYVLTCPDMLRKLRRSLRTVLESVLVDDSELGGAGSSRRRRTSSTARSASPLALCSRPEEPRGPARLLGWLLGSCAASPQTGPLNRALSSTSSSequence ID CRTH2 (nucleotide sequence (SEQ ID NO: 2): atgtcggccaacgccaca ctgaagccac tctgccccat cctggagcag atgagccgtc tccagagccacagcaacacc agcatccgct acatcgacca cgcggccgtg ctgctgcacg ggctggcctcgctgctgggc ctggtggaga atggagtcat cctcttcgtg gtgggctgcc gcatgcgccagaccgtggtc accacctggg tgctgcacct ggcgctgtcc gacctgttgg cctctgcttccctgcccttc ttcacctact tcttggccgt gggccactcg tgggagctgg gcaccaccttctgcaaactg cactcctcca tcttctttct caacatgttc gccagcggct tcctgctcagcgccatcagc ctggaccgct gcctgcaggt ggtgcggccg gtgtgggcgc agaaccaccgcaccgtggcc gcggcgcaca aagtctgcct ggtgctttgg gcactagcgg tgctcaacacggtgccctat ttcgtgttcc gggacaccat ctcgcggctg gacgggcgca ttatgtgctactacaatgtg ctgctcctga acccggggcc tgaccgcgat gccacgtgca actcgcgccaggcggccctg gccgtcagca agttcctgct ggccttcctg gtgccgctgg cgatcatcgcctcgagccac gcggccgtga gcctgcggtt gcagcaccgc ggccgccggc ggccaggccgcttcgtgcgc ctggtggcag ccgtcgtggc cgccttcgcg ctctgctggg ggccctaccacgtgttcagc ctgctggagg cgcgggcgca cgcaaacccg gggctgcggc cgctcgtgtggcgcgggctg cccttcgtca ccagcctggc cttcttcaac agcgtggcca acccggtgctctacgtgctc acctgccccg acatgctgcg caagctgcgg cgctcgctgc gcacggtgctggagagcgtg ctggtggacg acagcgagct gggtggcgcg ggaagcagcc gccgccgccgcacctcctcc accgcccgct cggcctcccc tttagctctc tgcagccgcc cggaggaaccgcggggcccc gcgcgtctcc tcggctggct gctgggcagc tgcgcagcgt ccccgcagacgggccccctg aaccgggcgc tgagcagcac ctcgagttag

Cell Culture and Transfection. COS-7 cells were grown in Dulbecco'smodified Eagle's medium (DMEM) 1885 supplemented with 10% fetal bovineserum, 100 units/ml penicillin, 1000 μg/ml streptomycin, and kept at 37°C. in a 10% CO₂ atmosphere. HEK293 cells were maintained in MinimumEssential medium (MEM) supplemented with 10% (v/v) heat inactivatedfetal calf serum (HIFCS), 2 mM Glutamax™-I, 1% non essential amino acids(NEAA), 1% sodium pyruvate and 10 μg/ml gentamicin. For bindingexperiments, COS7 cells were transiently transfected with the CRTH2receptor using a calcium phosphate-DNA coprecipitation method with theaddition of chloroquine (as described by Holst et al., 2001↓). Toperform the functional Bioluminescence Resonance Energy Transfer (BRET)assays, a HEK293 cell clone stably expressing βarr2-GFP² and CRTH2-Rlucwas generated (CRTH2-HEK293 cells).

Binding assay. 24 h after transfection COS-7 cells were seeded into 96well plates at a density of 30.000 cells/well. Competition bindingexperiments on whole cells were then performed about 18-24 h later using0.1 nM [³H]PGD2 (NEN, 172 Ci/mmol) in a binding buffer consisting ofHBSS (GIBCO) and 10 mM HEPES. Competing ligands were diluted in DMSOwhich was kept constant at 1% (v/v) of the final incubation volume.Total and nonspecific binding were determined in the absence andpresence of 10 μM PGD2. Binding reactions were routinely conducted for 3h at 4° C. and terminated by 2 washes (100 μl each) with ice coldbinding buffer. Radioactivity was determined by liquid scintillationcounting in a TOPCOUNTER (Packard) following over night incubation inMicroscint 20. Stable HEK293 cells were seeded at a density of 30.000cells/well 18-24 h prior to the binding assay which was performedessentially as described for COS7 cells above. Determinations were madein duplicates.

BRET assay. Functional BRET assays were performed on HEK293 cells stablyexpressing human CRTH2-Rluc and GFP²-β-arr2. Prior to their use in theBRET assay cells were detached and re-suspended in D-PBS with 1000 mg/LL-Glucose at a density of 2×10⁶ cells/mL. DeepBlueC™ was diluted to 50μM in D-PBS with 1000 mg/L L-Glucose (light sensitive). 100 μL of cellsuspension was transferred to wells in a 96-well microplate (whiteOptiPlate) and placed in the Mithras LB 940 instrument (BERTHOLDTECHNOLOGIES, Bad Wildbad, Germany). 12 μL/well agonist was theninjected by injector 1 and 10 μL/well DeepBlueC™ was injectedsimultaneously by injector 2. Five seconds after the injections thelight output from the well was measured sequentially at 400 nm and 515nm, and the BRET signal (mBRET ratio) was calculated by the ratio of thefluorescence emitted by GFP²-β-arr2 (515 nm) over the light emitted bythe receptor-Rluc (400 nm). Antagonists were added before placing themicroplates into the Mithras LB 940 and allowed to incubate for 15minutes prior to the addition of agonist and DeepBlueC™. Compounds weredissolved in DMSO and the final DMSO concentration was kept constant at1% in the assay.

Human eosinophil shape change assay. Blood was sampled from healthyvolunteers according to a protocol approved by the Ethics Committee ofthe University of Graz and processed as described previously (Bohm etal., 2004). Preparations of polymorphonuclear leukocytes (containingeosinophils and neutrophils) were prepared by dextran sedimentation ofcitrated whole blood and Histopaque gradients. The resulting cells werewashed and resuspended in assay buffer (comprising PBS with Ca²⁺/Mg²⁺supplemented with 0.1% BSA, 10 mM HEPES and 10 mM glucose, pH 7.4) at5×10⁶ cells/mL. Cells were incubated with the antagonists or vehicle(PBS or DMSO) for 10 min at 37° C. and then stimulated with variousconcentration of the agonists (PGD2 or eotaxin) for 4 min at 37° C. Tostop the reaction, samples were transferred to ice and fixed with 250 μLof fixative solution. Samples were immediately analyzed on a FACSCaliburflow cytometer (Becton Dickinson) and eosinophils were identifiedaccording to their autofluorescence in the FL-1 and FL-2 channels. Shapechange responses were quantified as percentage of the maximal responseto PGD2 or eotaxin in the absence of an antagonist.

Materials

Tissue culture media and reagents were purchased from the Gibcoinvitrogen corporation (Breda, Netherlands). PGD2 was obtained fromCayman and [3H]PGD2 from NEN.

Data Analysis

Curve analysis was performed with the GraphPadPrism software 3.0(Graphpad Prism Inc., San Diego, USA) and IC₅₀ values were calculated asa measure of the antagonistic potencies.

References

Hoist B, Hastrup H, Raffetseder U, Martini L, Schwartz T W. Two activemolecular phenotypes of the tachykinin NK1 receptor revealed byG-protein fusions and mutagenesis. J Biol Chem. 2001 Jun. 8;276(23):19793-9. Epub 2001 Feb. 22.

Biological Data:

Compounds were tested in the receptor binding assay and the functionalantagonist assay described below, and their IC₅₀ values were assessed.The compounds are grouped in three classes:

A: IC₅₀ value lower than 0.5 μM

B: IC₅₀ value between 0.5 μM and 5 μM

C: IC₅₀ value higher than 5 μM

Tables 1 to 7 give the biological test results for the compoundssynthesised above and for some additional compounds acquired fromcommercial sources. The ability of the compounds above to inhibitprostaglandin D2 induced eosihophil shape change is demonstrated by theexamples in FIG. 1.

TABLE 1

Binding Antag. A R1 R2 R3 R4 R5 R6 R7 R8 R9 X Y IC₅₀ IC₅₀ D1 COOH Br H HH H H H H H C C A A D2 COOH H H H H H H H H H C C A B D3 COOH F H H H HH H H H C C A B D4 Tetrazole Br H H H H H H H H C C A C D5 COOH Ph H H HH H H H H C C A A D6 COOH Br H H H H H H H — N C A A D7 COOH Br H H H HH OMe H H C C A A D8 COOH

H H H H H H H H C C A B D9 COOH

H H H H H H H H C C A A D10 COOH Cl H H H H H H H H C C A B D11 COOH MeH H H H H H H H C C A B D12 COOH Cl Me H H H H H H H C C B C D13 COOH ClH Cl H H H H H H C C C C D14 COOH Br H H H Cl H H H H C C C A D15 COOHBr H H H H Cl H H H C C A A D16 COOH Br H H H H H Br H H C C A A D17COOH Br H H H H H Cl H H C C A A D18 COOH Br H H H Et H H H H C C A AD19 COOH NO₂ H H H H H Cl H H C C A A D20 COOH NO₂ H H H H H H H H C C AA D21 COOH Br H H H Br H H H H C C A A D22 COOH Br H H H F H H H H C C AA D23 COOH Br H H H CF₃ H H H H C C A A D24 COOH Br H H H H Br H H H C CA A D25 COOH Br H H H H CF₃ H H H C C A A D26 COOH Br H H H Cl H Cl H HC C A A D27 COOH NO₂ H H H Cl H H H H C C A A D28 COOH NO₂ H H H Br H HH H C C A A D29 COOH Br H H H Cl H H H Cl C C A A D30 COOH Et H H H Br HH H H C C A A D31 COOH i-Pr H H H Cl H H H H C C A A D32 COOH Br H H H HH OCF₃ H H C C A A D33 COOH Br H H H Br H Br H H C C A A D34 COOH Br H HH Cl H Br H H C C A A D35 COOH Br H H H Cl H Cl H Cl C C A A D36 COOHOMe H H H H H H H H C C A B D37 COOH Br H H Me H H H H H C C A A (S)-D37COOH Br H H Me H H H H H C C A A D38 COOH Br H H Me Cl H H H H C C A AD39 COOH Br H H Me Cl H H H Cl C C A A D40 COOH Br H H H CN H H H H C CA A D41 COOH Br H H H OEt H H H H C C A A D42 COOH Br H H H Et H Br H HC C A A D43 COOH Br H H H OPh H H H H C C A A D44 COOH Br H H H SMe H HH H C C A A D45 COOH Br H H H Br H Me H H C C A A D46 COOH Br H H Me EtH Br H H C C A A D47 COOH Br H H Me OPh H H H H C C A A D48 COOH Br H HMe OEt H H H H C C A A D49 COOH Br H H Me SMe H H H H C C A A D50 COOHBr H H Me Br H Me H H C C A A D51 COOH Br H H Me OPh H H H H C C A A D52COOH Br H H H OCF₃ H H H H C C A A D53 COOH Et H H H Me H H H Me C C A AD54 COOH Br H H H Me H Me H H C C A A D55 COOH Br H H Me Me H Me H H C CA A D58 COOH Br H H H Me H Cl H H C C A A D59 COOH Br H H H Cl H H Cl HC C A A D60 COOH Br H H H OMe H H H H C C A A D61 COOH Br H H H H Cl ClH H C C A A D62 COOH Br H H Me Me H Cl H H C C A A D63 COOH Br H H Me ClH Cl H H C C A A D64 COOH Br H H Me H Cl Cl H H C C A A D65 COOH Br H HMe OMe H H H H C C A A D66 COOH NH₂ H H H H H H H H C C B A D67 COOH BrH H Me Cl H Br H H C C A A D68 COOH Br H H Me Cl H Cl H Cl C C A A D69COOH Br H H Me Br H Br H H C C A A D70 COOH Br H H H Et H H H Et C C A AD71 COOH Br H H H Me H H H Me C C A A D72 COOH Br H H H Et H H H Me C CA A D73 COOH Br H H H i-Pr H H H H C C A A D74 COOH EtO H H H H H H H HC C B C D75 COOH n-Bu H H H H H H H H C C A C D76 COOH Br H H H Cl H H HMe C C A A D77 COOH Br H H Me Me H H H Me C C A A D78 COOH Br H H Me EtH H H Et C C A A D79 COOH Br H H Me i-Pr H H H H C C A A D80 COOH Br H HH Cl H H H Cl C N A A D81 COOH Br H H H H H CF₃ H H C C A A

TABLE 2

Binding Antag. n X R1 R2 R3 R4 R5 IC₅₀ IC₅₀ D83 0 O H H H H H A C D84 0O H H OMe H H A B D85 0 O H H Cl H H A C D86 0 O H OMe H H H A A D87 0 OH H OEt H H A C D88 1 O H H H H H A A D89 1 O H OMe H H H A A D90 1 O ClH F H H A A D91 1 O Cl H H H Cl A A D92 1 O H H OMe H H A A D93 0 S H HH H H A A D94 1 S H H Cl H H A A

TABLE 3

Binding Antag. n R1 R2 R3 R4 R5 IC₅₀ IC₅₀ D99 0 H H H H H A A D100 0 H HF H H A A D101 0 H H OMe H H A A D102 0 H H Cl H H A A D103 0 H H OCF₃ HH A A D104 0 H OMe H H H A A D105 0 H Cl H H H A A D106 0 H H CF₃ H H AA D107 0 OMe H H H H A A D108 0 Cl H H H H A A D109 0 H CF₃ H CF₃ H A CD110 0 Cl H H H Cl A A D111 0 H H OPh H H A A D112 0 H CF₃ H H H A AD113 1 H H OCF₃ H H A A D114 1 H H Cl H H A A D115 1 H H H H H A A D1161 H H F H H A A D117 1 H F H F H A A D118 1 H H OMe H H A A D119 1 H OMeH H H A A D120 1 Cl H H H H A A D121 1 Cl H H H Cl A A D122 1 Cl H Cl HH A A D123 1 H Cl Cl H H A A D124 1 H OMe OMe H H A A D125 1 H OMe H H HA C D126 1 H H Me H H A A D127 1 CF₃ H H H H A A D128 1 H OMe H OMe H AB D129 0 Cl H Cl H H A A D130 1 H Cl H H H A A D131 1 H H NHAc H H A A

TABLE 4

Binding Antag. n R1 R2 R3 R4 R5 Activity IC₅₀ IC₅₀ D134 0 H H 4-PhOMe HH A A A D135 0 H H Cl H H A A A D136 0 H Cl H H H A A A D137 0 Cl H H HH A A A D138 0 H H H H H A A C

TABLE 5 Binding Antag. Structure IC₅₀ IC₅₀ D56

A A D57

A A D82

A A D95

A A D96

A B D97

A A D98

A D132

A A D133

A C

TABLE 6 Binding Antag. Structure IC₅₀ IC₅₀ D139

A A D140

A B D141

A A D142

A A D143

A A D144

A A D145

A A D146

A A

TABLE 7

Binding Antag. Cmp R1 R2 IC₅₀ IC₅₀ D149 H

A A D150 Br

A C D151 Br

A C D152 Br

A B D153 H

B C D154 H

A A D155 H

A B D156 H

A B

1. A method of treatment of disease responsive to modulation of CRTH2receptor activity comprising administering to a subject suffering suchdisease a compound of formula (I) or a salt, hydrate or solvate thereof:

wherein A represents a carboxyl group —COOH, or a carboxyl bioisostere;A₁ is hydrogen or methyl; ring Ar¹ is an optionally substituted phenylring or 5- or 6-membered monocyclic heteroaryl ring, in which AA₁CHO—and L2 are linked to adjacent ring atoms; rings Ar², Ar³ eachindependently represent a phenyl or 5- or 6-membered monocyclicheteroaryl ring, or a bicyclic ring system consisting of a 5- or6-membered carbocyclic or heterocyclic ring which is benz-fused or fusedto a 5- or 6-membered monocyclic heteroaryl ring, said ring or ringsystem being optionally substituted; t is 0 or 1; L2 and L3 eachindependently represent a divalent radical of formula—(Alk¹)_(m)—(Z)_(n)—(Alk²)_(p) wherein m, n and p are independently 0 or1, Alk¹ and Alk² are independently optionally substituted straight orbranched chain C₁-C₃ alkylene or C₂-C₃ alkenylene radicals which maycontain a compatible —O—, —S— or —NR— link wherein R is hydrogen orC₁-C₃ alkyl, and Z is —O—; —S—; —C(═O)—; —SO₂—; —SO—; —NR—, —NRSO₂—,—SO₂NR—, —C(═O)NR—, —NRC(═O)—, —NRCONH—, —NHCONR—, —NRC(═NR)NH—,—NHC(═NR)NR—, —C(R)═N—NR—, or —NR—N═C(R)— wherein R is hydrogen or C₁-C₃alkyl; or a divalent 5- or 6-membered monocyclic carbocyclic orheterocyclic radical, PROVIDED THAT (A) the total length of L2 and L3does not exceed that of an unbranched saturated chain of 10 carbonatoms; and (B) L2 is not —C(═O)—, —C(═O)NR—, or —NRC(═O)— when Ar² isoptionally substituted phenyl; and (C) (a) L2 is not a bond and (b) p inL2 is not 0 when n is 1 and Z is aryl or heteroaryl, and (D) (a) L2 isnot —O—, —SO₂—, —NR—, —CHR^(X)R^(Y)— or —CH(R^(X))(OR^(Y))—, whereinR^(x) and R^(Y) are independently hydrogen, halogen, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, or C₃-C₇ cycloalkyl, or join to form a ring, and(b) when p is 1 and n is 1 and Z is aryl or heteroaryl then Alk² is not—CHR^(X)R^(Y)— or —CH(R^(X))(OR^(Y))—, wherein R^(X) and R^(Y) areindependently hydrogen, halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, or C₃-C₇ cycloalkyl, or join to form a ring.
 2. A method asclaimed in claim 1, wherein, in the compound (I), (i) the length of eachof L2 and L3 does not exceed that of an unbranched saturated chain of 5carbon atoms and (ii) the total length of L2 and L3 does not exceed thatof an unbranched saturated chain of 7 carbon atoms, and (iii) neither ofL2 and L3 includes more than two R substituents different from hydrogen,3. A method as claimed in claim 1 wherein, in the compound (I), A_(l) ishydrogen and Z is —O—; —S—; —C(═O)—; —SO₂—; —SO—; —NR—, —NRSO₂——C(═O)NR—, —NRCONH—, —NRC(═NR)NH—, or —C(R)═N—NR—, wherein R is hydrogenor C₁-C₃ alkyl; or a divalent 5- or 6-membered monocyclic carbocyclic orheterocyclic radical.
 4. A method as claimed in claim 1 wherein, in thecompound (I), L2 is —N═CR—, —OCR₂C(═O)NR—N═CR—, —C(═O)NR—, —N═CR—,—C(═O)—, —CH═CHC(═O)—, —(CH₂)₀₋₃NRC(═O)—, —NRC(═O)(CH₂)₀₋₃—, —O—N═CH—,—CH₂NRCH₂—, —NR(CH₂)₁₋₃—, —(CH₂)₁₋₃NR—, —S—, —CH₂OCH₂—, —O(CH₂)₁₋₃—,—(CH₂)₁₋₃O—, —CH₂SCH₂—, —S(CH₂)₀₋₃—, —(CH₂)₀₋₃S—, a divalent(C₂-C₆)alkylene radical, a divalent (C₂-C₆)alkenylene radical, or adivalent (C₂-C₆)alkynylene radical, wherein R is hydrogen or C₁-C₃alkyl.
 5. A method as claimed in claim 1 wherein, in the compound (I),L2 is —NRN═CH—, —ON═CH—, or —N═CH—.
 6. A method as claimed in claim 1wherein, in the compound (I), L2 is —C(═O)—.
 7. A method as claimed inclaim 1 wherein, in the compound (I), L2 is —NHC(═O)— or —C(═O)NH—.
 8. Amethod as claimed in claim 1 wherein, in the compound (I), L2 is adivalent radical selected from one of the following formulae, whereineither (i) the bond marked * is attached to Ar² while the bond marked **is attached to Ar¹, or (ii) the bond marked * is attached to Ar¹ whilethe bond marked ** is attached to Ar²:

wherein R is hydrogen or C₁-C₃ alkyl.
 9. A method as claimed in claim 8wherein, in the compound (I), A1 is hydrogen and L2 has one of thefollowing formulae wherein the bond marked * is attached to Ar² whilethe bond marked ** is attached to Ar¹:

wherein R is hydrogen or C₁-C₃ alkyl.
 10. A method as claimed in claim 1wherein the disease is one associated with elevated levels ofprostaglandin D2 (PGD2) or one or more active metabolites thereof.
 11. Amethod as claimed in claim 1 wherein the disease is an inflammatory,autoimmune, respiratory or allergy disease.
 12. A method as claimed inclaim 1 wherein the disease is selected from asthma, rhinitis, allergicairway syndrome, allergic rhinobronchitis, bronchitis, chronicobstructive pulmonary disease (COPD), nasal polyposis, sarcoidosis,farmer's lung, fibroid lung, cystic fibrosis, chronic cough,conjunctivitis, atopic dermatitis, Alzheimer's disease, amyotrophiclateral sclerosis, AIDS dementia complex, Huntington's disease,frontotemporal dementia, Lewy body dementia, vascular dementia,Guillain-Barre syndrome, chronic demyelinating polyradiculoneurophathy,multifocal motor neuropathy, plexopathy, multiple sclerosis,encephalomyelitis, panencephalitis, cerebellar degeneration andencephalomyelitis, CNS trauma, migraine, stroke, rheumatoid arthritis,ankylosing spondylitis, Behçet's Disease, bursitis, carpal tunnelsyndrome, inflammatory bowel disease, Crohn's disease, ulcerativecolitis, dermatomyositis, Ehlers-Danlos Syndrome (EDS), fibromyalgia,myofascial pain, osteoarthritis (OA), osteonecrosis, psoriaticarthritis, Reiter's syndrome (reactive arthritis), sarcoidosis,scleroderma, Sjogren's Syndrome, soft tissue disease, Still's Disease,tendinitis, polyarteritis Nodossa, Wegener's Granulomatosis, myositis(polymyositis dermatomyositis), gout, atherosclerosis, lupuserythematosus, systemic lupus erythematosus (SLE), type I diabetes,nephritic syndrome, glomerulonephritis, acute and chronic renal failure,eosinophilia fascitis, hyper IgE syndrome, sepsis, septic shock,ischemic reperfusion injury in the heart, allograft rejection aftertransplantations, and graft versus host disease.
 13. A method as claimedin claim 1 wherein the disease is selected from asthma, rhinitis,allergic airway syndrome, and allergic rhinobronchitis,
 14. A method asclaimed in claim 1 wherein, in the compound (I), ring Ar² is (i) anoptionally substituted phenyl or naphthyl ring; (ii) a phenyl ring fusedto a 5- or 6-membered nitrogen-containing heterocyclic ring, either orboth of such rings being optionally substituted; (iii) an optionallysubstituted nitrogen-containing 5- or 6-membered heteroaryl ring; or(iv) a nitrogen-containing 5- or 6-membered heterocyclic ring fused to aphenyl ring, either of which rings being optionally substituted.
 15. Amethod as claimed in claim 14 wherein, in the compound (I), ring Ar² isoptionally substituted phenyl, pyridyl, pyrimidyl, diazolyl, thiazolyl,oxazolyl, triazinyl, quinolinyl, pyrrollyl, furanyl, thiazolyl.
 16. Amethod as claimed in claim 15 wherein, in the compound (I), optionalsubstituents in Ar² are selected from fluoro, chloro, bromo,(C₁-C₃)alkyl, trifluoromethyl, (C₁-C₃)alkoxy, trifluoromethoxy,trifluoromethylthio, dimethylamino, cyano, (C₁-C₃alkyl)SO₂—, NH₂SO₂—,(C₁-C3alkyl)NHSO₂—, (C₁-C₃alkyl)₂NSO₂—, and nitro.
 17. A method asclaimed in claim 1 wherein, in the compound (I), Ar¹ is a 5- or6-membered nitrogen-containing heteroaryl ring, optionally substituted.18. A method as claimed in claim 1 wherein in the compound (I), Ar¹ is aphenyl ring and L3 is linked to the 4-position thereof relative to theACHA₁O— radical.
 19. A method as claimed in claim 1 wherein in compound(I), t is 1 and Ar³ is a 5- or 6-membered heteroaryl ring, optionallysubstituted.
 20. A method as claimed in claim 1 wherein in compound (I),t is 1 and Ar³ is a phenyl ring, optionally substituted.
 21. A method asclaimed in claim 1 wherein in compound (I), any optional substituents inring Ar¹ or Ar³ are selected from fluoro, chloro, bromo, iodo, cyano,nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio,(C₁-C₃alkyl)SO₂—, NH₂SO₂—, (C₁-C₃alkyl)NHSO₂—, (C₁-C₃alkyl)₂NSO₂—, C₁-C₆alkyl, C₁-C₆ alkoxy, cycloalkyl, aryl, aryloxy, aryl(C₁-C_(6)—) oraryl(C₁-C₆ alkoxy)-.
 22. A method as claimed in claim 1 wherein incompound (I), t is 0 and L3 is a bond.
 23. A method as claimed in claim1 wherein, in the compound (I), A is —COOH.
 24. A method as claimed inclaim 1 wherein, in the compound (I), A is a carboxyl bioisostereselected from —SO₂NHR and —P(═O)(OH)(OR) wherein R is hydrogen methyl orethyl, —SO₂OH, —P(═O)(OH)(NH₂), —C(═O)NHCN and groups of formulae:


25. A method as claimed in claim 1 wherein, in the compound (I), A₁ ishydrogen.